Aims. To examine the effects of gender and acculturation on illicit drug use among the Mexican-origin population in California. Design. The 3012 subjects between 18 and 59 years of age were selected under a stratified, multi-stage cluster sampling method. Setting. Fresno County in California is primarily agricultural, with only one metropolitan area. Over 30% of the total population of 764 800, are Hispanics, of Mexican origin. Measurements. A modified version of the World Health Organization's Composite International Diagnostic Instrument (WHO-CIDI) was used to ascertain drug use. Respondents were considered drug users if they had ever used marijuana, cocaine, hallucinogens, heroin or inhalants. Acculturation was measured with a Likert scale, assessing English vs. Spanish language preference. Other covariates of interest were nativity and place of residence. Findings. Men had higher rates of use than women for every drug (men = 46.3%, women = 23.2%). Urban rates were higher than rural rates, for both women (urban = 32.8% vs. rural = 16.6%) and men (urban = 57.0% vs. rural = 36.8%). In logistic regression models, men were more likely than women to have ever used illicit drugs or inhalants (adjusted OR = 4.8), cocaine (adjusted OR = 5.3) or marijuana (OR = 4.3). However, the combined effect of United States nativity and acculturation, on drug use, was greater among women (adjusted OR = 29.3) than among men (adjusted OR = 7.4). The effect of acculturation was stronger among urban, than among town or rural residents. Conclusions. Acculturation and United States nativity are risk factors for illicit drug use among Mexican origin men and women. However, women have increased vulnerability compared with men. Findings reinforce the need for culturally based public health interventions.