We tested the hypothesis that a combination of measurements of different aspects of atherosclerosis, including burden of atherosclerosis and levels of inflammation, would contain more predictive information than either alone in an outpatient population. We enrolled 110 patients (62 +/- 15 years of age) who were referred to the noninvasive vascular laboratory for sequential Doppler pressure measurements of the lower extremities. We measured ankle-brachial index (ABI) and serum markers of inflammation and followed subjects for a mean of 2.25 years. Fifty subjects did not have peripheral arterial disease (PAD; ABI > or =0.9), whereas 60 did (ABI <0.9). Markers of inflammation, including C-reactive protein (3.83 +/- 0.9 vs 2.11 +/- 1.1, p = 0.019), were higher in subjects who had PAD. During follow-up, 42% developed an event (myocardial infarction, stroke, unplanned coronary or lower extremity revascularization, or death). Decreasing ABI (chi-square 7.3, p = 0.026) and increasing C-reactive protein (chi-square 22.1, p <0.001) increased the risk of an event. Risk increased sixfold between the lowest and highest groups for all events and fourfold for hard events (myocardial infarction, stroke, and death) using both C-reactive protein and ABI. In conclusion, patients who have PAD and increased inflammation are at highest risk for adverse cardiovascular outcomes. Characterizing atherosclerosis on the basis of these parameters provides important prognostic information.