The purpose of the study was to examine predictors of the leg hemodynamic response to exercise in middle- and older-aged men and women. Femoral artery blood flow (FBF), mean arterial pressure (MAP), and femoral vascular conductance (FVC, calculated as the quotient of FBF and MAP) were measured at rest and during 5 min of single knee-extensor exercise at ~10 W workload in healthy men (n = 31) and women (n = 32) (age 40-72 years). Age, menopausal status, maximal quadriceps strength, blood lipids, vitamin D levels, maximal oxygen uptake (VO(2max)), physical activity, blood pressure, estimated quadriceps muscle mass, and body mass index (BMI) were also assessed. The effect of age on FBF and FVC was negative and significant in men (r = -0.44 and -0.42 and p = 0.01 and 0.02, respectively) but was abolished by normalization to estimated quadriceps muscle (p = 0.18 and 0.73, respectively). There was no effect of age on leg hemodynamic responses to exercise in women (alone or normalized to quadriceps muscle), but menopausal status was a significant predictor of FVC and normalized FVC (p = 0.04 and 0.02, respectively). The multivariate model for exercising FVC in men (in order of strongest to weakest predictors) included quadriceps strength, BMI, resting FVC, age, and high-density lipoprotein cholesterol. The multivariate model for exercising FVC in women included quadriceps mass, systolic blood pressure, vitamin D, age, VO(2max), waist circumference, and physical activity score. These findings suggest that factors besides chronological age mediate exercising leg hemodynamics in middle-aged to older adults and that these factors are sex-specific.