OBJECTIVES: To study substance use and psychiatric disorders among prescription opioid users, heroin users, and non-opioid drug users in a national sample of adults. METHODS: Analyses of data from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (N=43,093). RESULTS: Four groups were identified among 9140 illicit or non-prescribed drug users: heroin-other opioid users (1.0%; used heroin and other opioids), other opioid-only users (19.8%; used other opioids but never heroin), heroin-only users (0.5%; used heroin but never other opioids), and non-opioid drug users (78.7%; used drugs but never heroin or other opioids). After adjusting for variations in socioeconomic characteristics, history of substance abuse treatment, and familial substance abuse, heroin-other opioid users had greater odds of several substance use disorders (cocaine, hallucinogen, sedative, amphetamine, and tranquilizer) as compared with the other groups; heroin-only users had reduced odds of sedative and tranquilizer use disorders as compared with other opioid-only users. Non-opioid drug users had reduced odds of all substance use disorders and other mental disorders (mood, anxiety, pathological gambling, and personality) as compared with other opioid-only users. Past-year other opioid-only users also reported slightly lower scores on quality of life than past-year non-opioid drug users. CONCLUSIONS: All opioid use groups had higher rates of substance use disorders than non-opioid drug users, and these rates were particularly elevated among heroin-other opioid users. Findings suggest the need to distinguish between these four groups in research and treatment as they may have different natural histories and treatment needs.