Background: In acute stroke, the magnetic resonance (MR) imaging-based mismatch concept is used to select patients with tissue at risk of infarction for reperfusion therapies. There is however a controversy if non-deconvolved or deconvolved perfusion weighted (PW) parameter maps perform better in tissue at risk prediction and which parameters and thresholds should be used to guide treatment decisions. Methods: In a group of 22 acute stroke patients with consecutive MR and quantitative positron emission tomography (PET) imaging, non-deconvolved parameters were validated with the gold standard for penumbral-flow (PF) detection 15O-water PET. Performance of PW parameters was assessed by a receiver operating characteristic curve analysis to identify the accuracy of each PWI map to detect the upper PF threshold as defined by PET cerebral blood flow <20 mL/100 g/min. Results: Among normalized non-deconvolved parameters, PW-first moment without delay correction (FM without DC) > 3.6 s (area under the curve [AUC] = 0.89, interquartile range [IQR] 0.85–0.94), PW-maximum of the concentration curve (Cmax) < 0.66 (AUC = 0.92, IQR 0.84–0.96) and PW-time to peak (TTP) > 4.0 s (AUC = 0.92, IQR 0.87–0.94) perform significantly better than other non-deconvolved parameters to detect the PF threshold as defined by PET. Conclusions: Non-deconvolved parameters FM without DC, Cmax and TTP are an observer-independent alternative to established deconvolved parameters (e.g., Tmax) to guide treatment decisions in acute stroke.