Diffusion-perfusion mismatch can be used to identify acute stroke patients that could benefit from reperfusion therapies. Early assessment of the mismatch facilitates necessary diagnosis and treatment decisions in acute stroke. We developed the RApid processing of PerfusIon and Diffusion (RAPID) for unsupervised, fully automated processing of perfusion and diffusion data for the purpose of expedited routine clinical assessment. The RAPID system computes quantitative perfusion maps (cerebral blood volume, CBV; cerebral blood flow, CBF; mean transit time, MTT; and the time until the residue function reaches its peak, Tmax) using deconvolution of tissue and arterial signals. Diffusion-weighted imaging/perfusion-weighted imaging (DWI/PWI) mismatch is automatically determined using infarct core segmentation of ADC maps and perfusion deficits segmented from Tmax maps. The performance of RAPID was evaluated on 63 acute stroke cases, in which diffusion and perfusion lesion volumes were outlined by both a human reader and the RAPID system. The correlation of outlined lesion volumes obtained from both methods was r2 = 0.99 for DWI and r2 = 0.96 for PWI. For mismatch identification, RAPID showed 100% sensitivity and 91% specificity. The mismatch information is made available on the hospital's PACS within 5–7 min. Results indicate that the automated system is sufficiently accurate and fast enough to be used for routine care as well as in clinical trials. J. Magn. Reson. Imaging 2010;32:1024–1037. © 2010 Wiley-Liss, Inc.