To develop personalized interventions and improve outcomes in substance-using populations, research is needed on the heterogeneity in substance use patterns and motivations that exists among adult substance users. This study took a person-centered approach to identify profiles of lifetime substance use and discern the psychosocial differences among them. To survey a spectrum of drug use severity, 1106 adults (43.4% women) were recruited from forensic and community samples. Participants reported on the frequency of lifetime substance use across multiple drug categories (sedatives, stimulants, marijuana, heroin, hallucinogens, misuse of prescription drugs) and alcohol use. Latent profile analysis was used to identify distinct profiles of substance use that were then compared on potential risk and maintenance factors for substance use. Four profiles of lifetime substance use emerged that diverged on severity of use and degree of mono vs. polysubstance use (Recreational Marijuana Use, Heavy Multidrug Intoxication, Heavy Marijuana Use, and Heavy Opioid and Polysubstance Use). The profiles differed on affective motivations for substance use (e.g., using to cope vs. using to seek a thrill), age of use onset, drug-related functional impairment, and experiences of childhood maltreatment. Cognitive functioning did not differentiate the heavy substance use profiles. Results provide compelling initial evidence that lifetime patterns of use can be used to identify groups of substance users with distinct risk and maintenance factors. Results highlight affective motivations for substance use and maltreatment history as potential treatment targets and underscore the importance of studying polysubstance use in the context of the opioid epidemic.