In this single-case research study, we examined the efficacy and acceptability of sertraline treatment in children diagnosed with selective mutism. We utilized a double-blind, placebo-controlled trial of sertraline within a replicated multiple baseline/across participants research design (n = 2; n = 3). Multiple methods of assessment involving across-setting informants were completed repeatedly throughout the 16-week study. Follow-up data was collected at 4 and 20 weeks poststudy. Assessment measures failed to demonstrate group changes in mutism, anxiousness, and shyness. All individuals realized considerable improvement on some of these variables. Two of the five participants no longer met diagnostic criteria for selective mutism following less than 10 weeks of 100 mg sertraline treatment. A third participant was reported asymptomatic at 20 weeks poststudy. Treatment compliance was high. Parent treatment acceptability ratings were highly favorable. Single-case research methodology has considerable clinical utility in the medication treatment of selective mutism. Frequent and repeated measurement across phases helped to highlight varying levels of participant improvement across situationally specific settings. Additional investigation of the use of selective serotonin reuptake inhibitors in treating selective mutism is warranted.