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American Indians (AIs) have often reported higher rates of drug use than have other racial/ethnic groups. However, the majority of these studies have focused on drug use among high school adolescents, with little attention to pathological use such as drug abuse or dependence. This study is among the first to report lifetime drug use and disorder (abuse/dependence) information from community samples of two culture groups of AI people—one in the Southwest (SW), one in the Northern Plains (NP)—ranging in age from 15 to 57 years old. Analyses were conducted within four groups: SW men, SW women, NP men, and NP women. Across the four groups, lifetime use rates for marijuana (36.9–57.5%), cocaine (4.3–21.5%), and inhalants (3.6–17.0%) were the highest drug use rates; heroin (0.5–2.1%), the lowest. Lifetime drug disorder rates were highest for marijuana (4.5–14.1%), cocaine (1.1–2.3%), and stimulants …