The objective of this study was to evaluate the efficacy and tolerability of atomoxetine hydrochloride (ATX) in the treatment of adults with atypical manifestations of attention-deficit hyperactivity disorder (ADHD) (not otherwise specified [NOS]). We hypothesized that treatment with ATX will be safe and efficacious for the treatment of adults with ADHD-NOS. This was a 6-week, open-label, prospective treatment study of ATX monotherapy in 45 adult patients with ADHD-NOS assessed using standardized instruments for diagnosis and a robust oral daily dose of up to 1.2 mg/kg/day or 120 mg/day. Symptom severity was assessed with the adult ADHD Investigator Symptom Report Scale (AISRS) and Clinical Global Impression Scale. Treatment with ATX at an average daily dose of 78.7 +/- 27.8 mg was associated with a statistically and clinically significant reduction in ADHD symptoms relative to baseline as assessed through the (AISRS) (-12.1 +/- 8.4; P < 0.001). Using a categorical definition of response (CGI-I much or very much improved), a majority (N = 29; 64%) of subjects were rated as improved at study endpoint. Treatment with ATX was relatively well tolerated. These open-label results suggest that ATX may be safe and effective in the treatment of adults meeting criteria for ADHD-NOS and support the need for further controlled clinical trials of ATX in this population.