The break was eventually hauled back inside the final hour of racing, with Enrico Battaglin (LottoNL-Jumbo) beating his fellow Italian Giovanni Visconti (Bahrain-Merida) to the line in Santa Ninfa. Simon Yates and Tim Wellens are slightly further back - 17 seconds and 19 seconds behind respectively.
Four riders - Ryan Mullen, Laurent Didier, Eugert Zhupa and Andrea Vendrame - were involved in an early breakaway.
Froome, who suffered a crash in a training ride before the Giro start in Jerusalem on Friday, added: "A lot of pure climbers who don't really fancy their chances in the time trial against (Tom) Dumoulin will be wanting to take time".
And so it proved.
Both riders still have big roles to play, however, with both teams having riders in the top 20 of the Giro standings.
The 26-year-old Wellens also won a Giro stage two years ago, and he topped the overall classification in the five-stage Vuelta Andalucia Ruta Ciclista del Sol in February.More news: Britain's environmental initiative could ban wet wipes
In their absence it was Wellens who looked to be running the show, the in-form Belgian sniffing out a second-successive win on the steep ramp preceding the finish.
"I wasn't in great position getting into the [finishing] climb", said Froome, who still has bruises on his right leg.
"We're only on the fifth stage but I already have a third and a first".
Froome came home much further back alongside team-mate Sergio Henao but in the same time as his rivals, the four-time Tour de France victor staying 55 seconds shy of Dennis on GC.
Rohan Dennis held onto the overall leader's pink jersey with a 1-second lead over defending champion Tom Dumoulin, with four-time Tour de France victor Froome 55 seconds back.