PurposeThis study examined if culturally and linguistically adapted versions of a US-developed adolescent substance use prevention intervention, keepin’ it REAL (kiREAL), for Mexico increases the use of drug resistance strategies and if increased use of resistance strategies subsequently leads to a reduction in the frequency of substance use (i.e., alcohol, cigarette, marijuana, and inhalants). MethodsStudents (N = 5,522, 49% female, age range = 11–17) in 36 middle schools across three cities in Mexico were randomized into three conditions: (1) Mantente REAL (MREAL), the culturally adapted version, (2) kiREAL-S, the linguistically adapted version, and (3) Control. Using survey data collected at four time points, random intercept cross-lagged path analyses tested the direct and indirect effects of MREAL and kiREAL-S compared to Control. ResultsAt time 2, the number of drug resistance strategies used by students increased in both MREAL (β = 0.103, p = .001) and kiREAL-S (β = 0.064, p = .002) compared to Control. However, only MREAL lead to less frequent use of alcohol (β = −0.001, p = .038), cigarettes (β = −0.001, p = .019), marijuana (β = −0.002, p = .030), and inhalants (β = −0.001, p = .021) at time 4, mediated through increased use of drug resistance strategies. DiscussionThis study provides evidence that MREAL and kiREAL-S are successful in spurring use of the drug resistance strategies that are the core component of the intervention. Only MREAL achieved long-term effects on substance use behaviors, the ultimate objective of these interventions. These findings provide support for the value and importance of rigorous cultural adaptation of efficacious prevention programs as a necessary condition for enhancing prevention benefits for participating youth.