<b><i>Background:</i></b> A number of large trials have confirmed the benefits of thrombolysis in acute stroke, but there are gender differences. We sought to examine the relationship between sex and outcome after thrombolysis. <b><i>Methods:</i></b> This was a prospective cohort study including 1,272 incident ischemic strokes (597 in women) from April 1, 2006 to December 31, 2014. Statistical approaches were used for analyzing survival outcomes and their relationship with thrombolysis therapy. <b><i>Results:</i></b> The death rates were lower (p = 0.003) in the thrombolysis therapy group with an incidence ratio of 0.57 (95% CI 0.39-0.83). 113 (8.8%) patients (53 women) received thrombolysis. They were significantly younger (69.2 ± 12.7 vs. 73.9 ± 12.5 years; p < 0.001), had higher NIHSS score (12.7 ± 6.3 vs. 7.3 ± 7.0; p < 0.001), spent more days in hospital (10.4 ± 8.3 vs. 8.3 ± 7.9; p < 0.001), and had a higher average Barthel score at discharge (85.5 ± 24.4 vs. 79.2 ± 28.6; p = 0.023). The male/female incidence ratio showed a significant decrease (p = 0.01) in the incidence of mortality in women and a better Barthel score. The thrombolysis improved the survival in the overall group with thrombolysis versus without thrombolysis (p = 0.028), in women versus in men with thrombolysis (p = 0.023), and in women with thrombolysis versus in those without thrombolysis (p < 0.001) but not in men with thrombolysis versus in those without thrombolysis (p = 0.743). The protective factors as regards mortality were thrombolysis therapy (95% CI 0.37-0.80; p = 0.002), Barthel score ≥60 (95% CI 0.81-0.94; p = 0.002), and cardiovascular secondary prevention 1 year after stroke (0.13, 95% CI 0.06-0.28). <b><i>Conclusions:</i></b> The stroke death rates were lower in women after thrombolysis treatment and suggest significant benefit for women in this setting. The overall benefit on survival of the patients treated with thrombolysis might be explained by the beneficial effect of the thrombolysis on the women.