Objective: To show that PET with 18F-fluoromisonidazole (18F-FMISO) can detect peri-infarct hypoxic tissue in patients after ischemic stroke. Background: PET with 15O-labeled oxygen and water is the only established method for identifying the ischemic penumbra in humans. We used PET with 18F-FMISO in patients after ischemic stroke to identify hypoxic but viable peri-infarct tissue likely to represent the ischemic penumbra, and to determine how long hypoxic tissues persist after stroke. Methods: Patients with acute hemispheric ischemic stroke were studied using PET with 18F- FMISO either within 48 hours or 6 to 11 days after stroke onset. The final infarct was defined by CT performed 6 to 11 days after stroke. Tracer uptake was assessed objectively by calculating the mean activity in the contralateral (normal) hemisphere, then identifying pixels with activity greater than 3 SDs above the mean in both hemispheres. Positive studies were those with high-activity pixels ipsilateral to the infarct. Results: Fifteen patients were studied; 13 within 48 hours of stroke, 8 at 6 to 11 days, and 6 during both time periods. Hypoxic tissue was detected in 9 of the 13 patients studied within 48 hours of stroke, generally distributed in the peripheries of the infarct and adjacent peri-infarct tissues. None of the 8 patients studied 6 to 11 days after stroke exhibited increased 18F-FMISO activity. All 6 patients studied both early and late exhibited areas of increased activity during the early but not the late study. Conclusions: PET with 18F-FMISO can detect peri-infarct hypoxic tissue after acute ischemic stroke. The distribution of hypoxic tissue suggests that it may represent the ischemic penumbra. Hypoxic tissues do not persist to the subacute phase of stroke (6 to 11 days).