OBJECTIVE Promethazine has been reported to be misused in conjunction with opioids in several settings. Promethazine misuse by itself or in conjunction with opioids may have serious adverse health effects. To date, no prevalence data for the nonmedical use of promethazine have been reported. This study examines the prevalence and correlates of promethazine use in 2 different populations in San Francisco, California: methadone maintenance clinic patients and community-based injection drug users (IDUs). METHODS We analyzed urine samples for the presence of promethazine and reviewed the clinical records for 334 methadone maintenance patients at the county methadone clinic. Separately, we used targeted sampling methods to recruit and survey 139 community-based opioid IDUs about their use of promethazine. We assessed prevalence and factors associated with promethazine use with bivariate and multivariate statistics. RESULTS The prevalence of promethazine-positive urine samples among the methadone maintenance patients was 26%. Only 15% of promethazine-positive patients had an active prescription for promethazine. Among IDUs reporting injection of opiates in the community-based survey, 17% reported having used promethazine in the past month; 24% of the IDUs who reported being enrolled in methadone treatment reported using promethazine in the past month. CONCLUSIONS The finding that one-quarter of methadone maintenance patients in a clinic or recruited in community settings have recently used promethazine provides compelling evidence of significant nonmedical use of promethazine in this patient population. Further research is needed to establish the extent and nature of nonmedical use of promethazine.