Background and Purpose—This study aimed to test the explanatory qualities of the Stroke-Thrombolytic Predictive Instrument (S-TPI) when applied to patients treated in routine practice. Methods—S-TPI predictions were compared with observed outcomes in terms of normal/near-normal (modified Rankin Scale score, ≤1) and catastrophic outcome (modified Rankin Scale score, ≥5) at 3 months. Logistic regression was used to calibrate and expand the S-TPI. Results—The S-TPI overestimated probability of catastrophic outcomes and overestimated the probability of a normal/near normal outcome above 0.4 and underestimated those below. Calibrating the S-TPI minimized discrepancies between predicted and observed outcomes, in the case of normal/near-normal outcomes, where including additional predictors (serum glucose and signs of current infarction on pretreatment brain scan) further reduced discrepancies between predicted and observed outcomes. Conclusions—The explanatory power of the S-TPI in thrombolytic-treated patients can be improved to reflect outcomes seen in routine practice.