BACKGROUND: Little is known about the influence of sex on the course of attention-deficit/hyperactivity disorder (ADHD) and its comorbid psychiatric conditions. The purpose of this study was to examine the effect of sex on the course and psychiatric correlates of ADHD from childhood into adolescence. METHODS: Two identically designed, longitudinal, case-control family studies of male and female probands with and without ADHD and their siblings were combined. All subjects were blindly assessed with structured diagnostic interviews. Among subjects with a lifetime history of ADHD (n = 471, mean age 11.5 +/- 4.3 years at baseline), we used linear growth curve models to estimate the effect of time on the change in ADHD symptoms, and whether this effect differed by sex. We also we examined the effect of sex on the association between ADHD and the longitudinal progression of comorbid psychopathology using structural equation models. RESULTS: We found no evidence that sex moderated the effect of age on ADHD symptoms; in both genders, age exhibited a similar effect on the decline of ADHD symptoms. However, the female sample demonstrated greater stability in comorbid psychopathology from childhood into adolescence. Furthermore, we found that the stability of comorbid psychopathology in females remained significant after accounting for the correlation between adolescent psychopathology and adolescent ADHD. In males, childhood and adolescent comorbid psychopathology were no longer correlated when adolescent ADHD was taken into account. CONCLUSIONS: Our findings indicate that while the course of ADHD across childhood and adolescence did not differ between males and females, patterns of psychiatric comorbidity were conditional on sex. Future studies should explicitly test how sex modifies the associations between ADHD and risk factors and ADHD and associated functional outcomes.