Methamphetamine and cocaine use have been associated with a vulnerability to HIV infection among men who have sex with men and among men who have sex with women but not specifically among Mexican migrants in the United States. The California-Mexico Epidemiological Surveillance Pilot was a venue-based targeted survey of male and female Mexican migrants living in rural and urban areas in California. Among men (n = 985), the percentage of methamphetamine/cocaine use in the past year was 21% overall, 20% in male work venues, 19% in community venues, and 25% in high-risk behavior venues. Among women, 17% reported methamphetamine/cocaine use in high-risk behavior venues. Among men, methamphetamine/cocaine use was significantly associated with age less than 35 years, having multiple sex partners, depressive symptoms, alcohol use, sexually transmitted infections (including HIV), and higher acculturation. Prevention interventions in this population should be targeted to specific migrant sites and should address alcohol, methamphetamine, and cocaine use in the context of underlying psychosocial and environmental factors.