The present study was intended to examine the efficacy of immediate-release methylphenidate (MPH IR) in the treatment of adults with attention-deficit hyperactivity disorder (ADHD) under consideration of subtype according to DSM-IV criteria and psychiatric comorbidity. After baseline assessment over 3 weeks, 47 patients aged 18-59 years with combined ADHD (ADHD-C) (n=27) and predominantly inattentive ADHD (ADHD-I; n=20) were treated in an open, uncontrolled design with an average dose of 0.5 mg MPH IR per kg over 7 weeks. Thirty-nine patients finished the study. The two groups did not differ in response to treatment with regard to ADHD symptoms (very good to good outcome in ADHD-C 73.9%, in ADHD-I 66.7%) or cognitive measures (sustained attention, information processing speed, divided attention). However, ADHD patients with psychiatric comorbidities had significantly worse outcome: total ADHS scores on the T2 Brown Attention Deficit Disorder Scales (BADDS) were 66.2+/-15.5 with psychiatric comorbidity and 51.7+/-13.7 without (P=0.04), despite significantly higher doses of MPH IR (0.56+/-0.17 mg/kg vs 0.46+/-0.13 mg/kg; P=0.004). This effect was mainly seen in the patients with clinically significant depressive symptoms (Beck Depression Inventory > or =18), who clearly benefited less from treatment (total T2 BADDS scores with depressive symptoms 70.7+/-15.9 and without depressive symptoms 48.1+/-21.2; P=0.001).