Background: Intravenous thrombolysis with alteplase for ischemic stroke is fixed at a maximal dose of 90 mg for safety reasons. Little is known about the clinical outcomes of stroke patients weighing >100 kg, who may benefit less from thrombolysis due to this dose limitation. Methods: Prospective data on 1,479 consecutive stroke patients treated with intravenous alteplase in six Swiss stroke units were analyzed. Presenting characteristics and the frequency of favorable outcomes, defined as a modified Rankin scale (mRS) score of 0 or 1, a good outcome (mRS score 0-2), mortality and symptomatic intracranial hemorrhage (SICH) were compared between patients weighing >100 kg and those weighing ≤100 kg. Results: Compared to their counterparts (n = 1,384, mean body weight 73 kg), patients weighing >100 kg (n = 95, mean body weight 108 kg) were younger (61 vs. 67 years, p < 0.001), were more frequently males (83 vs. 60%, p < 0.001) and more frequently suffered from diabetes mellitus (30 vs. 13%, p < 0.001). As compared with patients weighing ≤100 kg, patients weighing >100 kg had similar rates of favorable outcomes (45 vs. 48%, p = 0.656), good outcomes (58 vs. 64%, p = 0.270) and mortality (17 vs. 12%, p = 0.196), and SICH risk (1 vs. 5%, p = 0.182). After multivariable adjustment, body weight >100 kg was strongly associated with mortality (p = 0.007) and poor outcome (p = 0.007). Conclusion: Our data do not suggest a reduced likehood of favorable outcomes in patients weighing >100 kg treated with the current dose regimen. The association of body weight >100 kg with mortality and poor outcome, however, demands further large-scale studies to replicate our findings and to explore the underlying mechanisms.