Objective Among ischemic stroke patients with negative CT angiography (CTA), we aimed to determine the predictive value of enhanced distal vessel occlusion detection using CT perfusion postprocessing (waveletCTA) for the treatment effect of IV thrombolysis (IVT). Methods Patients were selected from 1,851 consecutive patients who had undergone CT perfusion. Inclusion criteria were (1) significant cerebral blood flow (CBF) deficit, (2) no occlusion on CTA, and (3) infarction confirmed on follow-up. Favorable morphologic response was defined as smaller values of final infarction volume divided by initial CBF deficit volume (FIV/CBF). Favorable functional outcome was defined as modified Rankin Scale score of <= 2 after 90 days and decrease in NIH Stroke Scale score of >= 3 from admission to 24 hours (Delta NIHSS). Results Among patients with negative CTA (n = 107), 58 (54%) showed a distal occlusion on waveletCTA. There was no difference between patients receiving IVT (n = 57) vs supportive care (n = 50) regarding symptom onset, early ischemic changes, perfusion mismatch, or admission NIHSS score (all p > 0.05). In IVT-treated patients, the presence of an occlusion was an independent predictor of a favorable morphologic response (FIV/CBF: beta -1.43;95% confidence interval [CI] -1.96, -0.83;p = 0.001) and functional outcome (90-day modified Rankin Scale: odds ratio 7.68;95% CI 4.33-11.51;p = 0.039;Delta NIHSS: odds ratio 5.76;95% CI 3.98-8.27;p = 0.013), while it did not predict outcome in patients receiving supportive care (all p > 0.05). Conclusion In stroke patients with negative CTA, distal vessel occlusions as detected by waveletCTA are an independent predictor of a favorable response to IVT.