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Narrow inclusion criteria regarding substance use are commonplace in clinical research. This is due, in part, to assumptions about capacity to make “rational” decisions regarding participation by these populations. This study evaluated decision-making and perceptions surrounding each of the Belmont principles among individuals with cocaine use histories, cigarette smokers without illicit substance use histories, and controls without cigarette or illicit substance use histories. Cocaine (n = 124), cigarette (n = 128), and control (n = 145) groups were recruited using Amazon’s Mechanical Turk. Participants completed measures evaluating research participation after reading two hypothetical study vignettes varying in risk. Assays assessed capacity to consent, perceived research burden, and endorsement of research participation by various populations. Individuals reporting cocaine use showed a reduced capacity to consent compared to controls, but this effect was small and largely explained by sociodemographic differences (e.g., race) rather than substance use history. Perceived research burden in the cigarette group was lower than in the cocaine group, but this difference was of a small to medium effect size. All groups reported substantively lower endorsement of research participation by individuals with illicit substance use histories relative to healthy adults, with less support indicated by control and cigarette groups compared to the cocaine group. Few differences were observed by substance use history regarding perceptions of and decision-making surrounding research participation. These data highlight the need for the continued study of evidence-based ethics and support more widespread acceptance of research participation by individuals with substance use histories in clinical research.