Cyperus difformis L. is one of the worst weeds of rice world-wide and has evolved resistance to acetolactate synthase (ALS)-inhibiting herbicides in rice fields of California. Propanil use was intensified to control the widespread resistant biotypes. Rice growers have recently experienced poor control, suggesting resistance to this photosystem II-inhibiting herbicide may have evolved in C.difformis populations. The objectives of this study were to detect the presence of propanil resistance, to establish resistance levels, and to investigate involvement of enhanced herbicide detoxification as mechanism of resistance through the use of metabolic inhibitors. Four C.difformis populations collected in rice fields from the Sacramento Valley of California were confirmed resistant to propanil. This is the first case of such resistance outside the Poaceae and the first time C.difformis exhibits resistance to an herbicide mechanism of action other than ALS inhibition. Carbaryl and malathion applied individually in mixture with propanil had minor effects on herbicide toxicity suggesting metabolic detoxification was not a resistance mechanism. A resistant biotype produced more than 80% biomass after a propanil (6.7kg a.i. ha^-1) and carbaryl (1.9kg a.i. ha^-1) or propanil and malathion (1.0kg a.i. ha^-1) treatment compared to <20% by a susceptible biotype, suggesting substantial resistance still persisted in spite of insecticide addition. Propanil-resistant plants were cross-resistant to bensulfuron-methyl, imazosulfuron, halosulfuron-methyl and penoxsulam, but susceptible to carfentrazone. The loss of propanil to control this important weed of rice underscores the fragility of herbicide-based weed control in monoculture rice. Integrated weed management approaches to decrease herbicide selection pressure are needed to mitigate the evolution of multiple-herbicide resistance in C.difformis of California rice.