Enrico Battaglin (LottoNL-Jumbo) improved on his third place from 24 hours previous by taking the steep uphill finish into Santa Ninfa. After surfing the wheel of Giovanni Visconti (Bahrain-Merida) into the final corner before rounding him in the final hundred metres for victory.
Behind Jose Goncalves (Katusha-Alpecin) rounded out the podium just ahead of young German Max Schachmann (Quick-Step Floors).
The final 1,500 metres saw plenty of riders shelled due to the high pace set by Mitchelton-Scott and Bahrain-Merida but the majority of General Classification riders finished safely in the bunch.
The only big loser was Miguel Angel Lopez (Astana) who found himself losing the best of a minute thanks to a crash in the final 5km.
Rohan Dennis (BMC Racing) managed to weather the storm in Sicily holding on to pink ahead of tomorrow's first mountain stage to Mount Etna.
Giro d'Italia Stage 5: The day as it went
Stage 5 of the 2018 Giro d'Italia kept the peloton on the island of Sicily for its penultimate day with a 153km route from Agrigento to Santa Ninfa. The day largely hugged the coast of the Mediterranean Sea rolling constantly with three classified climbs en route.
As soon as the flag dropped in Agrigento the attacks begun. Ryan Mullen (Trek-Segafredo) was the first to try his luck with Andrea vendrame (Androni-Sidermec) and Eugert Zhupa (Wilier-Triestina) close to hand.
Eventually these three forged a gap alongside Laurent Didier (Trek-Segafredo) to form the day's break.
The gap kept growing maxing out at around 5 minutes 30 seconds with race leader Dennis's BMC Racing assuming the chase with Team Sunweb and Lotto-Fix All.
Rather methodically, the gap then began to drop and was quickly reeled down to 3 minutes 30 for the final 100km.
Little happened for an extended period of time. The General Classification riders clearly had an eye on tomorrow's stage to Mount Etna while others were clearly feeling the pinch of a hectic first four stages.
The first climb of the day at Santa Margherita di Belice was taken by Vendrame from Zhupa. The break then rolled through the intermediate sprint with Elia Viviani (Quick-Step Floors) the best of the rest, extending his lead in the sprinters' competition.
By the 50km to go marker, the work of Lotto-Fix All and Groupama-FDJ had brought the gap down to a manageable 2 minutes 40 with the peloton seemingly able to bring back those ahead at will.
For some, including myself, today's stage seemed like perfect terrain for a breakaway with constant undulation and the first mountain stage tomorrow holding the attention of the main favourites however the presence of the top teams clearly suggested otherwise.
A few slips in the bunch, notably for Steve Morabito (Groupama-FDJ) and Laurens Ten Dam (Team Sunweb) reminded us of the constant threat and also allowed the break to bring their gap back out to over 2 minutes.
As the break dipped under two minutes, Didier attacked from teammate Mullen's wheel with the two Italian riders taking chase.
Didier was caught with Vendrame going over the top alone. Zhupa took Didier's wheel as the duo took chase. The bunch behind slashed the lead down to 90 seconds while the Androni man Vendrame took the points on the final climb of the day.
The gap between Vendrame and the peloton dropped to one minute as the race entered its final 15km. Lotto-Fix All were doing the lion's share of the work behind for a clearly confident Tim Wellens who fancied his chances of repeating yesterday's win.
With 12.7km to go a large crash halted many of the peloton yet thankfully none of the General Classification were downed by the coming together, except Domenico Pozzovivo (Bahrain-Merida) who found himself chasing back onto the peloton with teammate Manuele Boaro.
Mitchelton-Scott began to drive the pace in the final 5km while Lopez found himself riding into an adjacent field although 'Superman' managed to remount and begin his chase back to the bunch.
As the peloton reached the final 4km Vendrame was caught and the big players jostled out for the stage victory.