Background: Reports on worldwide drug use include some information on risk factors, but virtually no information on protective factors, which are an important component of prevention programs. Aims: This study investigated protective factors and biological sex differences associated with patterns of substance use among adolescents in Myanmar, a country in Southeast Asia. Method: Myanmar high school students (N = 1,918; M[subscript age] = 15.35, SD = 1.07, range = 14-18; 56% female) completed a version of the "Communities That Care" survey validated for use in this population. Results: Latent class analysis revealed "Low Users" (38%), "Normative Users" (47%), and "Poly Drug Users" (15%) classes for males, and "Low Users" (80%), "Glue/Over-the-Counter Medication Users" (14%), and "High Users" (6%) classes for females. Univariate analyses indicated that belief in the moral order and positive family attachment differentiated profiles for both males and females; opportunities for prosocial family involvement, prosocial peer behavior, and opportunities to talk with teachers were additionally significant for males only. Logistic regression analysis comparing males in the "Low Users" and "Normative Users" classes indicated that opportunities for prosocial family involvement was protective after accounting for significant demographic and risk factors. In contrast, analyses comparing other classes of males or females found that once significant demographic and risk factors were controlled, protective factors did not discriminate classes. Conclusions: These data suggest that sex-specific prevention and intervention strategies may be more successful than universal approaches, and that attention to both risk and protective factors in prevention programming is warranted.