Background and Purpose-Stroke is the third leading cause of death and the leading cause of adult disability in the United States. The clot-lysis drug tissue plasminogen activator is the only treatment that has ba:en effective for acute stroke patients, yet there are significant limitations to its use and effectiveness. In this study retrograde transvenous neuroperfusion (RTN) was evaluated for its efficacy in reversing acute ischemia, preventing paralysis, and limiting pathological evidence of infarction in baboons. Methods-Ten adult male baboons underwent 3.5 hours of reversible middle cerebral artery occlusion (MCAO) under isoflurane (0.25% to 1.5%) anesthesia. Five randomly chosen animals received RTN treatment 1 hour after start of MCAO. Somatosensory evoked potentials were recorded during MCAO. Animals were assigned daily neurological scores. Animals were killed 6 days after MCAO, and brains were quantitatively analyzed for infarct volume. Results-Within 1 hour after RTN was started, treated animals showed significantly improved somatosensory evoked potentials (103.3% versus 75% of baseline; P<0.01). Likewise, the combined neurological score for the RTN-treated group was 99.2, while the combined mean score for the untreated group was 66.4 (P<0.015). The mean infarction volume was 8.8+/-3.1% (of contralateral hemisphere) for the control group and 0.3+/-0.2% for the RTN-treated group (P<0.01). No increased mortality was seen in the RTN-treated group. Conclusions-We conclude that RTN treatment during MCAO effectively reverses the pathophysiological sequelae of ischemia, even when the treatment is initiated 1 hour after the onset of ischemia. Although the infarct volume in the control group was variable when quantitatively assessed 6 days after 3.5 hours of MCAO, virtually no evidence of infarcts was seen in the RTN-treated group.