It happened after midnight on Fresno-Coalinga Road and El Dorado Avenue, south of Five Points.
California Highway Patrol officers say the driver of the truck carrying tomatoes ran the stop sign at Oakland Avenue, which is connected to both roads.
The tomato truck collided with a semi carrying grapes that had turned.
The crash caused a massive spill at the intersection.
The grape truck was T-boned, and the driver of the tomato truck was pinned inside his cab.
He was freed from the truck and flown by helicopter to a Fresno hospital with major injuries.
The other driver was not hurt.
Officers say the scene should be cleaned up soon, and traffic has not been affected.