Pyroxasulfone (KIH-485) is a seedling growth-inhibiting herbicide developed by Kumiai America that has the potential to control weeds in sunflower. However, little is known about how this herbicide will interact with various soil types and environments when combined with sulfentrazone. The objective of this research was to evaluate sunflower injury and weed control with pyroxasulfone applied with and without sulfentrazone across the Great Plains sunflower production area. A multisite study was initiated in spring 2007 to evaluate sunflower response to pyroxasulfone applied PRE at 0, 167, 208, or 333 g ai ha−1. In 2008, pyroxasulfone was applied alone and in tank mixture with sulfentrazone. In 2007, no sunflower injury was observed with any rate of pyroxasulfone at any location except Highmore, SD, where sunflower injury was 17%, 4 wk after treatment (WAT) with 333 g ha−1. In 2008, sunflower injury ranged from 0 to 4% for all treatments. Adding sulfentrazone did not increase injury. Sunflower yield was only reduced in treatments in which weeds were not effectively controlled. These treatments included the untreated control and pyroxasulfone at 167 g ha−1. Sunflower yield did not differ among the other treatments of pyroxasulfone or sulfentrazone applied alone or in combination. The addition of sulfentrazone to pyroxasulfone improved control of foxtail barley, prostrate pigweed, wild buckwheat, Palmer amaranth, and marshelder, but not large crabgrass or green foxtail. The combination of pyroxasulfone and sulfentrazone did not reduce control of any of the weeds evaluated.