The authors examine methadone plasma levels in 31 depressed methadone-maintained opiate addicts enrolled in a 12-week placebo-controlled, double-blind study of sertraline. Between baseline and week 6, patients on sertraline showed a mean increase in methadone plasma level/dose (P/D) ratio of 26% (SD = 43%, range -32% to +118%), while patients on placebo showed a mean decrease of 16% (SD = 27%, range -62% to +50%). This difference was significant (p < 0.02). The sertraline and placebo groups did not differ in reported side effects or methadone dose adjustments. Between weeks 6 and 12, methadone P/D in the sertraline group decreased back towards baseline, and the treatment groups did not differ significantly at week 12. The results suggest sertraline may produce a modest increase in methadone serum levels over the first six weeks of treatment. Depression and anxiety disorders are common in methadone-maintained patients. Serotonin uptake inhibitors are attractive choices for treatment due to their low toxicity and low abuse potential, but these agents variously inhibit isoenzymes responsible for the metabolism of methadone. Clinicians treating depressed or anxious methadone patients with second-generation antidepressants should monitor for clinical signs of increased or decreased methadone levels and consider monitoring serum methadone levels.