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Background: Methamphetamine dependence and associated medical and psychiatric concerns are significant public health issues. This project evaluated the efficacy of sertraline (50mg bid) and contingency management (CM) for the treatment of methamphetamine dependence., Method: In this randomized, placebo-controlled, double-blind trial, participants completed a 2-week non-medication baseline and were randomized to one of four conditions for 12 weeks: sertraline plus CM (n=61), sertraline-only (n=59), matching placebo plus CM (n=54), or matching placebo-only (n=55). All participants attended clinic thrice-weekly for data collection, medication dispensing, and relapse prevention groups. Outcomes included methamphetamine use (urine drug screening and self-reported days of use), retention (length of stay), drug craving (visual analogue scale), and mood symptoms (Beck Depression Inventory)., Results: No statistically significant main or interaction effects for sertraline or CM in reducing methamphetamine use were observed using a generalized estimating equation (GEE), although post hoc analyses showed the sertraline-only condition had significantly poorer retention than other conditions (chi(2) (3)=8.40, p<0.05). Sertraline conditions produced significantly more adverse events than placebo conditions. A significantly higher proportion of participants in CM conditions achieved three consecutive weeks of methamphetamine abstinence than those in non-CM conditions., Conclusions: These data do not demonstrate improved outcomes for sertraline versus placebo for treatment of methamphetamine dependence; indeed, they suggest sertraline is contraindicated for methamphetamine dependence. Findings provide support for the use of contingency management for treatment of methamphetamine dependence.