Background: Depression is common among individuals with methamphetamine (MA) use disorders. As agents that enhance serotonergic function are frequently used to treat depression, one might predict that they would be useful medications for MA dependence. However, clinical trials of serotonergic agents for MA addiction have been unsuccessful. Objective: To identify factors that distinguish MA-dependent research participants who increased MA self-administration while receiving treatment with the selective serotonin reuptake inhibitor (SSRI) sertraline from other groups of participants. Method: Using a dataset from a 12-week randomized, placebo-controlled trial of sertraline (100. mg daily) for MA addiction, we identified participants who had completed at least 8 weeks of the trial (n= 61 sertraline, n= 68 placebo). We compared the proportions of MA-positive urine tests for weeks 8-12 of the trial for these subjects to their pre-randomization baseline, and identified those subjects who increased MA use during treatment. Using classification trees, we then assessed all data collected during the study to identify factors associated with increasing MA use during treatment with sertraline, compared to placebo. Results: More subjects in the sertraline condition increased MA use during treatment (n= 13) than in the placebo condition (n= 5; p= 0.03). Classification trees identified multiple factors from both pre-treatment and in-treatment data that were associated with increased MA use during treatment. Only elevated in-treatment craving for MA specifically characterized subjects in the sertraline group who increased their MA use. Conclusions: Some MA-abusing individuals treated with SSRIs have sustained craving with an increased propensity to relapse during treatment despite psychosocial treatment interventions. © 2011.