Management of Italian ryegrass in cereal-based cropping systems continues to be a major production constraint in areas of the United States, including the soft white winter wheat producing regions of the Pacific Northwest. Pyroxasulfone is a soil-applied herbicide with the potential to control broadleaf and grass weed species, including grass weed biotypes resistant to group 1, 2, and 7 herbicides, in several crops for which registration has been completed or is pending, including wheat, corn, sunflower, dry bean, and soybean. Field experiments were conducted from 2006 through 2009 near Corvallis, OR, to evaluate the potential for Italian ryegrass control in winter wheat with applications of pyroxasulfone. Application rates of PRE treatments ranged from 0.05 to 0.15 kg ai ha−1. All treatments were compared to standard Italian ryegrass soil-applied herbicides used in winter wheat, including diuron, flufenacet, and flufenacet + metribuzin. Visual evaluations of Italian ryegrass and ivyleaf speedwell control and winter wheat injury were made at regular intervals following applications. Winter wheat yields were quantified at grain maturity. Ivyleaf speedwell control was variable, and Italian ryegrass control following pyroxasulfone applications ranged from 65 to 100% and was equal to control achieved with flufenacet and flufenacet + metribuzin treatments and greater than that achieved with diuron applications. Winter wheat injury from pyroxasulfone ranged from 0 to 8% and was most associated with the 0.15–kg ha−1 application rate. However, this early-season injury did not negatively impact winter wheat yield. Pyroxasulfone applied at the application rates and timings in these studies resulted in high levels of activity on Italian ryegrass and excellent winter wheat safety. Based on the results, pyroxasulfone has the potential to be used as a soil-applied herbicide in winter wheat for Italian ryegrass management and its utility for management of other important grass and broadleaf weeds of cereal-based cropping systems should be evaluated.