Objective: To compare the ADHD combined/hyperactive subtype (ADHD/CH) to the ADHD inattentive subtype (ADHD/I) on the level of comorbidity, treatment response, and possible etiological factors. Method: A total of 371 clinically referred children diagnosed with ADHD aged between 6 and 12 years are recruited for a double-blind, placebo-controlled trial of methylphenidate. Comorbidity, treatment response, and stress during pregnancy are assessed for each participant. Genotyping is done for the DAT, DRD4, and 5-HTT genes. Mothers report smoking or alcohol consumption during their pregnancy and their child’s birth weight. Results: The ADHD/CH children show both a higher frequency of conduct disorder and good response to treatment, are exposed to more moderate stress during their mothers’ pregnancy, and show a higher frequency of L/L genotype for the 5-HTT-linked polymorphic region. Conclusion: The significant differences found between the ADHD/CH and the ADHD/I subtypes raise the possibility that the two may be separate disorders.