Objective: Symptoms of depression and anxiety are commonly comorbid with attention-deficit/hyperactivity disorder (ADHD). The authors assessed the safety and effectiveness of atomoxetine monotherapy compared with combined atomoxetine/fluoxetine therapy in a population of children and adolescents with ADHD and concurrent symptoms of depression or anxiety. Method: Patients were randomized to treatment with fluoxetine (n = 127) or placebo (n = 46) under double-blind conditions for 8 weeks, with concomitant atomoxetine use the last 5 weeks. Results: At end point, reductions in ADHD, depressive, and anxiety symptoms were marked for both treatment groups (p < .001 for the relevant scale in each symptom cluster). Some differences between treatment groups for depressive symptoms were significant, but the magnitudes of the differences were small and likely of limited clinical importance. Completion rates for the two groups were similar, as were discontinuation rates for adverse events. The combination group had greater increases in blood pressure and pulse than did the monotherapy group. Conclusions: In pediatric patients with ADHD and comorbid symptoms of depression or anxiety, atomoxetine monotherapy appears to be effective for treating ADHD. Anxiety and depressive symptoms also improved, but the absence of a placebo-only arm does not allow us to conclude that these effects are specifically the result of treatment with atomoxetine. Combined atomoxetine/fluoxetine therapy was well tolerated.