Background: For adults in general population community settings, data regarding long-term course and outcomes of illicit drug use are sparse, limiting the formulation of evidence-based recommendations for drug use screening of adults in primary care. Objective: To describe trajectories of three illicit drugs (cocaine, opioids, amphetamines) among adults in community settings, and to assess their relation to all-cause mortality. Design: Longitudinal cohort, 1987/88 - 2005/06. SETTING: Community-based recruitment from four cities (Birmingham, Chicago, Oakland, Minneapolis). Participants: Healthy adults, balanced for race (black and white) and gender were assessed for drug use from 1987/88-2005/06, and for mortality through 12/31/2008 (n∈=∈4301) Measurements: Use of cocaine, amphetamines, and opioids (last 30 days) was queried in the following years: 1987/88, 1990/91, 1992/93, 1995/96, 2000/01, 2005/06. Survey-based assessment of demographics and psychosocial characteristics. Mortality over 18 years. RESULTS: Trajectory analysis identified four groups: Nonusers (n∈=∈3691, 85.8%), Early Occasional Users (n∈=∈340, 7.9%), Persistent Occasional Users (n∈=∈160, 3.7%), and Early Frequent/Later Occasional Users (n∈=∈110, 2.6%). Trajectories conformed to expected patterns regarding demographics, other substance use, family background and education. Adjusting for demographics, baseline health status, health behaviors (alcohol, tobacco), and psychosocial characteristics, Early Frequent/Later Occasional Users had greater all-cause mortality (Hazard Ratio, HR∈=∈4.94, 95% CI∈=∈1.58-15.51, p∈=∈0.006). Limitations: Study is restricted to three common drugs, and trajectory analyses represent statistical approximations rather than identifiable "types". Causal inferences are tentative. Conclusions: Four trajectories describe illicit drug use from young adulthood to middle age. Two trajectories, representing over one third of adult users, continued use into middle age. These persons were more likely to continue harmful risk behaviors such as smoking, and more likely to die. © 2011 Society of General Internal Medicine.