Background: The long-term health consequences of drug use among healthy young adults in the general population are not well described. We assessed whether drug use predicted decline in general self-rated health (GSRH) in a community-based cohort, healthy at baseline. Methods: A prospective cohort of 3124 young adults (20-32 years old) from four US cities, the Coronary Artery Risk Development in Young Adults Study, was followed from 1987/1988 to 2000/2001. All reported "Good" or better GSRH at baseline, with reassessment in 2000/2001. Drug use in 1987/1988 was as follows: 812 participants were Never Users; 1554 Past Users Only; 503 Current Marijuana Users Only; 255 Current Hard Drug Users (e.g. cocaine, amphetamines, opiates). Analyses measured the association of drug use (1987/1988) with decline to "Fair" or "Poor" GSRH in 2000/2001, adjusting for biological and psychosocial covariates. Results: Reporting health decline were: 7.2% of Never Users; 6.5%, Past Use Only; 7.0%, Current Marijuana Only; 12.6%, Current Hard Drugs (p < 0.01). After multivariable adjustment, Current Hard Drug Use in 1987/1988 remained associated with health decline (Odds Ratio (OR), referent Never Use: 1.83, 95% confidence interval (CI) 1.07-3.12). The health decline associated with Current Hard Drugs appeared to be partly mediated by tobacco smoking in 2000/2001, which independently predicted health decline (OR 1.66, 95% CI 1.08-2.50) and weakened the apparent effect of Current Hard Drugs (OR 1.21, 95% CI 0.62-2.36). Conclusions: Hard drug use in healthy young adults, even when hard drug use stops, is associated with a subsequent decrease in general self-rated health that may be partially explained by persistent tobacco use. © 2006 Elsevier Ireland Ltd. All rights reserved.