Over the past 20 years, we have observed a paucity of morbidity and mortality due to cardiovascular disease among drug users in a methadone maintenance clinic. The present study investigated whether long-term exposure to opiates or opioids is associated with decreased severity of coronary artery disease (CAD) by comparing 98 decedents with methadone or opiates (M/O) in their blood at autopsy with 97 frequency-matched decedents without M/O. Severe CAD was found significantly less often in M/O-positive decedents (5 of 98) than in M/O-negative decedents (16 of 97). Multiple logistic regression analysis contrasting those with moderate or severe CAD to those with no or mild CAD yielded an odds ratio of 0.43 (95% confidence interval 0.20 to 0.94) for M/O positivity after adjustment for potential confounding. Long-term opiate exposure thus may mitigate CAD severity and its often fatal consequences.