Pulmonary arterial hypertension (PAH) is a female-predominant disease, but there are little data on treatment response by sex and menopausal status. In this retrospective analysis of the Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) randomized clinical trial, we assessed treatment response between the sexes by examining change in 6-minute walk distance (6MWD) and time to clinical worsening (TCW). We examined the effect of menopausal status on the same treatment measures. 6MWD was recorded before and after 16 weeks of treatment with tadalafil or placebo in the PHIRST study cohort of 340 subjects (264 females, 76 males). A univariate analysis was used to assess the effect of sex on change in 6MWD and TCW. Multivariate linear regression and Cox proportional hazards models were built for 6MWD and TCW, respectively. Women were subdivided by age as a surrogate for menopausal status. The linear trend test and the log-rank test were performed on change in 6MWD and TCW by age. For tadalafil-treated patients, a significant difference in change in 6MWD by sex (mean: 48.6 m for males vs. 34.7 m for females; P = 0.01) was found, but it was not significant in multivariate analysis (P = 0.08). There was a trend toward a female age-dependent effect in change in 6MWD; the premenopausal group showed the greatest improvement. A significant sex- or age-dependent effect on TCW was not present. In conclusion, this retrospective analysis of the PHIRST trial suggests that men and premenopausal women may experience greater functional improvement when treated with tadalafil than older women, but there was no consistent sex or menopausal effect on TCW.