Perfusion-diffusion (PWI-DWI) mismatch may represent the ischemic penumbra. The complexities associated with perfusion-weighted imaging (PWI) have restricted its use. Mismatch between stroke severity, assessed with the National Institutes of Health Stroke Scale (NIHSS), and the volume of the diffusion-weighted imaging (DWI) lesion (clinical-diffusion mismatch; CDM) has been suggested as a surrogate for PWI-DWI mismatch. We compared CDM with PWI and DWI in acute stroke. Seventy-nine hemispheric stroke patients were imaged within 24 hours of symptom onset and subacutely (3 to 5 days). CDM was defined as NIHSS > or =8 and DWI < or =25 mL. DWI lesion and PWI (Tmax+4s) volumes were measured by planimetric techniques. Acute PWI-DWI mismatch was examined as a continuous variable (mismatch volume=PWIvol-DWIvol) and a categorical variable (mismatch=PWIvol-DWIvol/DWIvol x 100>20%). Early infarct expansion was calculated as DWI(subacute vol/DWI(acute vol). In the 54 sub-6-hour patients, CDM detected PWI-DWI mismatch with a specificity of 93% (95% confidence interval [CI], 62% to 99%), a positive predictive value of 95% (95% CI, 77% to 100%), but a sensitivity of only 53% (95% CI, 34% to 68%). Alternate DWI and NIHSS cutpoints did not improve test performance characteristics. In addition, subacute DWI expansion was significantly greater in patients with CDM (P=0.01) compared with those without. CDM (NIH > or =8, DWI < or =25 mL) predicts the presence of PWI-DWI mismatch with high specificity and low sensitivity. CDM also predicts DWI expansion. CDM may be a useful selection tool in acute stroke therapies, including thrombolysis.