BACKGROUND: Sarcopenia, commonly determined by measuring skeletal muscle mass index (SMI) at the third lumbar level, has been identified as a predictor of clinical outcome in a variety of diseases. For patients with peripheral arterial occlusive disease (PAOD), we hypothesized that lower extremity SMI (LESMI) might be a more precise predictor of outcome and the extent of chronic ischemia than the systemic muscle mass at the L3 level. We investigated the association between complete muscle volume and muscle area derived with single-slice 2-dimensional measurements in the legs to identify at which level cross-sectional single-slice measurements are most representative of the muscle volume and investigated whether LESMI is associated with systemic sarcopenia and PAOD severity. METHODS: Muscle volumes and areas were semiautomatically segmented from computed tomography (CT) scans of the affected and contralateral legs of 50 PAOD patients with Fontaine stage IIb and 50 PAOD patients with Fontaine stage IV. The muscle mass was determined for the complete volumes of the upper and lower legs and for cross-sectional slices at 40%, 50%, and 60% of the length of the femur and tibia. Patients were determined as sarcopenic based on sex-specific cut-off values at the L3 spinal segment. Two observers segmented 20 randomly selected patients to determine the interobserver reliability with the intraclass correlation coefficient. RESULTS: The correlation between the LESMI of the complete muscle volume and the three cross-sectional slices in all 200 upper and 200 lower legs was moderately strong to strong. Interobserver reliability of cross-sectional slice segmentation was excellent. The LESMI, both measured volumetrically and cross-sectionally, were significantly lower in patients with sarcopenia compared to patients without sarcopenia. The LESMI was lower in patients with Fontaine stage IV compared to patients with Fontaine stage IIb for both volumetric and cross-sectional measurements. CONCLUSIONS: Segmentation of skeletal muscle mass from cross-sectional single-slice CT in the upper and lower leg can accurately and precisely substitute complete volume segmentations. These findings warrant the use of measurements based on cross-sectional single-slice CT for assessing the LESMI. Patients with systemic sarcopenia are also at increased risk for muscle mass loss in the lower extremities. In the current study, LESMI was lower in patients with Fontaine class IV PAOD compared to patients with Fontaine class IIb PAOD. Future studies should assess the predictive value of the LESMI on clinical outcomes in PAOD patients.