With inter-county travel restrictions lifted, the Road Safety Authority and An Garda Síochána are asking all road users to take care and be more alert.
The 'Road Back' campaign is calling on road users to be extra cautious as traffic volumes return to normal.
More cars are back on the road, and with the significantly increased numbers of pedestrians and cyclists over the last year, the RSA said the need to always be on the lookout for other road users is essential.
The latest Transport Bulletin from the Central Statistics Office, published today, said the volume of cyclists during off-peak for April 2021 was 111% higher than the same month last year.
Road Safety Authority CEO Sam Waide said: "We know that it might be the first time back on the roads for a lot of people, so we encourage you to put safety first by checking your tyres, oil and lights.
"Get your mind in gear for driving again so that the road back is a safer place for everyone."
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An Garda Síochána said it appreciates that the vast majority of road users act responsibly when driving but even a slight lapse in concentration can have very serious results.
To date in 2021, a total of 45 people have died on Irish roads, which is eight fewer than the same period in 2020.
"You never know when a pedestrian might step off the pavement or a cyclist might need to avoid an obstacle", Chief Superintendent Ray McMahon of National Roads Policing said. "It's about expecting the unexpected and reading the road ahead.
"We are reminding drivers to remember the simple things - keep within speed limits, make sure to put your seatbelt on before setting off.
"Put your phones away and stay focused on the road ahead, remaining vigilant of vulnerable road users."
Car owners are also being advised to undertake some basic maintenance checks to ensure their vehicle is roadworthy, as it may not have been driven for some time.
"It is positive news to see the relaxation of travel restrictions", said Minister of State Hildegarde Naughton.
"We have all worked so hard to get this public health crisis under control and can now look forward to getting back on the road and enjoying inter-county travel once again, but we need to put safety first."
This is the first weekend people will be able to travel across the country since the Christmas period.
Large numbers of people are expected to take the roads so the message is to put safety first.