The Irish Nurses and Midwives Organisation has accepted Labour Court proposals aimed at resolving the dispute over pay and staff shortages.
The margin was 62% in favour, with 38% voting to reject them.
The dispute had triggered three days of strike action earlier this year.
The union's 37,000 members had been balloting on the package of measures over recent weeks.
INMO General Secretary Phil Ní Sheaghdha noted that the Government had committed to full implementation of the proposals, and the union would be seeking an immediate meeting to ensure this happens without delay.
She said INMO nurses and midwives had fought hard for patient safety and staffing in a "determined, controlled and collective manner".
The Minister for Health, Simon Harris, has welcomed the outcome of the ballot.
He said he believes the recommendations are good for both the nursing and midwifery profession and the health service.
The INMO had argued that only an across the board pay rise of around 12%, bringing members into line with other graduate health professionals like physiotherapists, would suffice to encourage nurses to enter and stay in the profession amid significant difficulties in recruitment and retention of staff.
However, last year the Public Service Pay Commission rejected that argument, opting instead for a €20m a year package of enhanced allowances targeted at the areas worst affected by staff shortages.
That option was rejected, leading to industrial action, with a significant impact on thousands of patients whose operations and outpatient appointments were cancelled.
A deal was eventually done that involves the introduction of a higher-paid Enhanced Nurse Practice grade, which nurses could join after reaching their fourth incremental point.
It also provided for more widespread distribution of allowances, some of which were increased.
The Department of Public Expenditure and Reform calculated the cost of the deal at up to €50m for 2019 and 2020, but stressed that was conditional on significant productivity and cost-offsetting savings being secured from measures in a new nursing contract.
While the INMO initially rejected the management's contract proposals, which sought the ability to vary shifts and redeploy staff potentially within the same day, the Labour Court ultimately recommended a new contract that the union's leadership said had eliminated the key points of contention for them.
The Government's pay policy is facing serious challenges.
Public service pay accounts for around a third of Government expenditure and the current Public Service Stability Agreement was intended to deliver a three-year window of certainty on pay until the end of 2020 by allocating around €900m for phased restoration of austerity pay cuts.
However, the INMO deal alone has clearly boosted the public service bill by at least €50m by the end of 2020 and even more if the Government fails to secure those cost-offsetting productivity measures from the nursing and midwifery grades.
The bill could rise further, as almost 6,000 psychiatric nurses belonging to the Psychiatric Nurses' Association are also in dispute over pay and staff shortages. That row has yet to be resolved, but it would be reasonable to assume that it too will see pay increases in one form or another.
In addition, numerous unions have already indicated that they will expect similar increases through knock-on claims.
Separately, 17,000 health sector support staff belonging to SIPTU are balloting for strike action in a dispute over job evaluation schemes. That too is likely to result in additional pay costs for the Government.
A further "add-on" to the original PSSA pay envelope involves the proposals to address the two-tier pay system affecting so-called new entrants recruited since 2011 on lower pay scales, which have been costed at €200m by 2026.
Just last week, Minister for Education Joe McHugh told the teachers' conferences that the Government was prepared to accept that even that deal left "unfinished business" and that the Government was prepared to give "full consideration" to the issue in any talks process that might arise.
However, he was silent on what mechanism, such as a mid-term pay review, might be involved, and when new entrants might see a further improvement on pay.
At the time, the Department of Public Expenditure and Reform cautioned that there was no commitment to address issues outside the current pay agreement "at this time".
There is now mounting speculation that a mid-term review will be announced shortly, not least in a bid to streamline the various pay demands.
A further issue of contention lies in the fact that despite clearly breaching the industrial peace clause of the PSSA, the INMO has not been penalised with an increment freeze and other penalties that were imposed on the ASTI teachers' union when it went on strike in 2016 over two-tier pay.
The ASTI has now threatened to sue the Government over this disparity of treatment.
It has lodged complaints against the Government with the International Labour Organisation and the European Committee of Social Rights.