Background: Few clinical stroke studies examine the effect of biologic sex on outcome. The Secondary Prevention of Small Subcortical Strokes (SPS3) study examined the effect of aspirin (asa) vs aspirin + clopidogrel (a+c) and higher (130-149 mmHg) vs lower (<130 mmHg) blood pressure goals in secondary stroke prevention. The purpose of this study was to assess sex differences in the primary and secondary outcomes in SPS3. Methods: Analyses included all participants randomized into the SPS3 clinical trial. Primary and secondary outcomes were assessed for differences within and between the female and male groups by both antiplatelet and blood pressure goal intervention. An interaction effect was assessed for both interventions to examine the effect of sex on outcome. Results: Of the males (n=1902) and females (n=1118) enrolled, significant differences in baseline demographics were: age, baseline SBP, race, smoking, hypertension, hyperlipidemia, HbA1c, LDL, HDL, and total cholesterol (analyses were adjusted). For the antiplatelet intervention, 1869 males (957 asa, 945 a+c) and 1118 females (546 asa, 572 a+c) were enrolled. Within males, there was a significant difference in all-cause mortality (1.54% asa vs 2.18% a+c, HR 1.44, p=0.04) and vascular cause mortality (0.52% asa vs. 1.00% a+c,HR 1.91, p=0.03). Within females, there was a significant difference in other thromboembolic events (0.15% asa vs. 0.66% a+c, HR 4.38, p=0.02) and all-cause mortality (1.2% asa vs. 2.04% a+c, HR 1.71, p=0.04). Sex did not have a significant effect on the primary outcome of stroke recurrence in the antiplatelet arm (p=0.91). For the blood pressure goal intervention, 1902 males (990 higher, 912 lower) and 1118 females (529 higher, 589 lower) were enrolled. There were no differences in outcomes within the male groups. There was a significant increase in other thromboembolic events in the higher (0.67%) vs lower (0.18%) females (HR 0.28, p=0.03). Sex did not have a significant effect on the primary outcome of stroke recurrence (p=0.50). Conclusion: Overall, there was no significant effect of sex on outcome in the SPS3 study. This analysis supports the use of standard antiplatelet secondary prevention and blood pressure management in both men and women.