Weeds are a major problem for rice production in California, and late watergrass (Echinochloa phyllopogon (Stapf) Koss) is one of the most serious weeds in water-seeded rice. Severe infestations can reduce yields by more than 50%. Flooding only partially controls this weed; thus, farmers rely heavily on herbicides. Resistance to several herbicides, including bispyribac-sodium, an acetolactate synthase (ALS) inhibitor not yet commercially used, has developed in late watergrass populations of California rice. Knowing the mechanisms of bispyribac resistance is relevant to designing herbicide management strategies for delaying resistance development to enhance the successful introduction of this new herbicide. We examined whether an insensitive ALS and cyt P-450-dependent detoxification were possible resistance mechanisms in a bispyribac-sodium-resistant (R) late watergrass population collected in California rice fields, which was previously determined to be resistant to molinate, thiobencarb, and fenoxaprop-ethyl. ALS activity was assayed on leaf extracts from young R and susceptible (S) plants for a range of bispyribac-sodium concentrations, and cross-resistance to another ALS inhibitor, bensulfuron-methyl, was evaluated using whole-plant bioassays. Resistance was not due to reduced ALS sensitivity to bispyribac-sodium in R plants, although the R accession was highly cross-resistant to bensulfuron-methyl. Although S and R plants had similar ALS activity (mg acetoin mg protein−1) without herbicide, more (P < 0.05) leaf protein was extracted from R (5.35 mg g−1 leaf fresh weight) than from S (3.19 mg g−1) plants, and general ALS activity (mg acetoin g leaf fresh weight−1) for all herbicide concentrations was higher in R than in S plants. The cyt P-450 inhibitors piperonyl butoxide and malathion were used for detection of herbicide degradation by cyt P-450 monooxygenation. The addition of these inhibitors strongly enhanced herbicide phytotoxicity toward R plants, suggesting that metabolic degradation of bispyribac-sodium contributed significantly to the observed resistance.