Importance: Limited empirical research has examined the extent to which cohort-level prevalence of substance use is associated with the onset of drug use and transitioning into greater involvement with drug use. Objective: To use cross-national data to examine time-space variation in cohort-level drug use to assess its associations with onset and transitions across stages of drug use, abuse, dependence, and remission. Design, Setting, and Participants: The World Health Organization World Mental Health Surveys carried out cross-sectional general population surveys in 25 countries using a consistent research protocol and assessment instrument. Adults from representative household samples were interviewed face-to-face in the community in relation to drug use disorders. The surveys were conducted between 2001 and 2015. Data analysis was performed from July 2017 to July 2018. Main Outcomes and Measures: Data on timing of onset of lifetime drug use, DSM-IV drug use disorders, and remission from these disorders was assessed using the Composite International Diagnostic Interview. Associations of cohort-level alcohol prevalence and drug use prevalence were examined as factors associated with these transitions. Results: Among the 90027 respondents (48.1% [SE, 0.2%] men; mean [SE] age, 42.1 [0.1] years), 1 in 4 (24.8% [SE, 0.2%]) reported either illicit drug use or extramedical use of prescription drugs at some point in their lifetime, but with substantial time-space variation in this prevalence. Among users, 9.1% (SE, 0.2%) met lifetime criteria for abuse, and 5.0% (SE, 0.2%) met criteria for dependence. Individuals who used 2 or more drugs had an increased risk of both abuse (odds ratio, 5.17 [95% CI, 4.66-5.73]; P <.001) and dependence (odds ratio, 5.99 [95% CI, 5.02-7.16]; P <.001) and reduced probability of remission from abuse (odds ratio, 0.86 [95% CI, 0.76-0.98]; P =.02). Birth cohort prevalence of drug use was also significantly associated with both initiation and illicit drug use transitions; for example, after controlling for individuals' experience of substance use and demographics, for each additional 10% of an individual's cohort using alcohol, a person's odds of initiating drug use increased by 28% (odds ratio, 1.28 [95% CI, 1.26-1.31]). Each 10% increase in a cohort's use of drug increased individual risk by 12% (1.12 [95% CI, 1.11-1.14]). Conclusions and Relevance: Birth cohort substance use is associated with drug use involvement beyond the outcomes of individual histories of alcohol and other drug use. This has important implications for understanding pathways into and out of problematic drug use.