Resistance to protoporphyrinogen oxidase (protox)-inhibiting herbicides was identified in a population of common waterhemp that had been treated with acifluorfen for several years. The protox-resistant biotype of common waterhemp was approximately 34, 82, 8, and 4 times more resistant than a susceptible common waterhemp biotype to acifluorfen, lactofen, fomesafen, and sulfentrazone, respectively. The resistant biotype also showed a high level of resistance to acetolactate synthase–inhibiting herbicides thifensulfuron and imazethapyr but not to glyphosate or paraquat. An organophosphate insecticide was applied with acifluorfen or lactofen to determine if metabolism could be the mechanism of resistance. No differences were observed between resistant plants treated with an organophosphate plus a protox-inhibiting herbicide and plants treated with a protox-inhibiting herbicide alone.