The purpose of this study was to characterize the neuropsychological profiles of adult patients with attention deficit hyperactivity disorder (ADHD) alone and ADHD with active comorbid depression, and to evaluate changes in the neuropsychological profile in these two groups following a trial of methylphenidate. Forty patients with ADHD were classified into two groups based on their affective status resulting in a group of 21 patients with ADHD alone and 19 patients with ADHD and active comorbid symptoms of depression (ADHD-D). All subjects received a comprehensive neuropsychological evaluation including measures of cognitive, motor and affective functioning before and after treatment. Fifteen normal controls were also assessed at a yoked time interval. At baseline, both patient groups showed impairment in verbal memory, motor and processing speed, visual scanning, and auditory and visual distractibility. Following treatment, both patient groups showed improvement across all neuropsychological measures while controls remained relatively stable over time. Improvement in neuropsychological test performance was not related to gender, affective status or referral source. Patients with active comorbid symptoms of depression show a similar neuropsychological profile and appear equally likely to benefit from methylphenidate intervention as patients with ADHD alone.