Background and Purpose— The Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) established guidelines to increase safety in acute stroke thrombolysis, but precluding treatment in an important proportion of patients. We aimed to assess safety/efficacy of thrombolysis in patients with SITS-MOST exclusion criteria. Methods— 369 nonlacunar tPA-treated patients were studied. Patients were classified as SITS-MOST (SM) or non–SITS-MOST (NSM) according to SITS-MOST–criteria fulfilling. Clinical evaluation was assessed by NIHSS and functional outcome by mRS at 3 months (functional independency=mRS ≤2). Results— Baseline NIHSS was 17. 169 (45.8%) patients were SM and 200 (54.1%) NSM. Recanalization (47.6%/50.3%, P =0.36), 24-hour-improvement (55.6%/49.5%, P =0.114), and SICH were similar (4.8%/5.1%, P =0.554). At discharge, clinical improvement in SM-group was higher (66.7%/55.7%, P =0.024). NSM tended to higher mortality (10.5%/16.1%, P =0.084) and lower functional independence (48.7%/39.6%, P =0.082). Conclusion— Thrombolysis may be safe in patients not fulfilling SITS-MOST criteria. Testing thrombolysis in patients outside SITS-MOST could be considered in the future.