A process for hydroprocessing heavy oil feedstock is disclosed. The process operates in once-through mode, employing a plurality of contacting zones and at least a separation zone to convert at least a portion of the heavy oil feedstock to lower boiling hydrocarbons, forming upgraded products. In the once-through upgrade system, little if any of the unconverted material and slurry catalyst mixture is recycled back to the system for further upgrading. The contacting zones operate under hydrocracking conditions, employing a slurry catalyst for upgrading the heavy oil feedstock. The slurry catalyst feed comprises an active metal catalyst having an average particle size of at least 1 micron in a hydrocarbon oil diluent, at a concentration of greater than 500 wppm of active metal catalyst to heavy oil feedstock.