Background and Purpose General anesthesia (GA) for endovascular therapy (EVT) of acute ischemic stroke (AIS) may be associated with worse outcomes. Methods The IMS III trial randomized patients within 3hrs of AIS onset to IV t-PA±EVT. GA use within 7hrs of stroke onset was recorded per protocol. Good outcome was defined as 90day mRS≤2. A multivariable analysis adjusting for dichotomized NIHSS (8-19 versus ≥20), age, and time from onset to groin puncture was performed. Results Four hundred thirty-four patients were randomized to EVT, 269(62%) were treated under local anesthesia and 147(33.9%) under GA; 18(4%) were undetermined. The two groups were comparable except for median baseline NIHSS (16 local anesthesia versus 18 [GA], p<0.0001). The GA group was less likely to achieve a good outcome (adjusted-RR 0.68, CI 0.52-0.90; p=0.0056) and had increased in-hospital mortality (adjusted-RR 2.84, CI 1.65-4.91; p=0.0002). Those with medically indicated GA had worse outcomes (adjusted RR 0.49, CI 0.30-0.81, p=0.005) and increased mortality (RR 3.93, CI 2.18-7.10; p<0.0001) with a trend for higher mortality with routine GA. There was no significant difference in the adjusted risks of SAH (p=0.32) or symptomatic ICH (p=0.37). Conclusions GA was associated with worse neurological outcomes and increased mortality in the EVT arm; this was primarily true among patients with medical indications for GA. Relative risk estimates, though not statistically significant, suggest reduced risk for SAH and sICH under local anesthesia. Although the reasons for these associations are not clear, these data support the use of local anesthesia when possible during EVT.