The crash happened at about 8 a.m. Tuesday on U.S. 131 in Kent County's Plainfield Township, about seven miles north of Grand Rapids.
Authorities identified the victims as John Pomeroy, 49, and William Kochis, 30.
Police said there was a traffic backup on southbound U.S. 131 and the men's car stopped, but a fast-moving pickup didn't brake and slammed into the car.
Police said the 57-year-old Sparta man driving the pickup was among several people who were injured.
Seven vehicles in all were involved in the crash, which remains under investigation.