Late watergrass [ Echinochloa phyllopogon (Stapf.) Koss.] is a major weed of California rice that has evolved P450-mediated metabolic resistance to multiple herbicides. Resistant (R) populations are also poorly controlled by the recently introduced herbicide penoxsulam. Ratios (R/S) of the R to susceptible (S) GR(50) (herbicide rate for 50% growth reduction) ranged from 5 to 9. Although specific acetolactate synthase (ALS) activity was 1.7 higher in R than in S plants, the enzyme in R plants was about 6 times more susceptible to the herbicide. R plants exhibited faster (2.8 times) oxidative [(14)C]-penoxsulam metabolism than S plants 24 h after treatment. Addition of malathion (P450 inhibitor) enhanced herbicide phytotoxicity and reduced penoxsulam metabolism in R plants. Tank mixtures with thiobencarb (can induce P450) antagonized penoxsulam toxicity in R plants, suggesting penoxsulam may be broken down by a thiobencarb-inducible enzyme. These results suggest E. phyllopogon resistance to penoxsulam is mostly due to enhanced herbicide metabolism, possibly via P450 monooxidation.