Peak oxygen consumption (V_ O2peak) is reduced in patients with chronic kidney disease (CKD). Although cardiovascular and skeletal muscle factors are implicated in the declines of V_ O2peak, few studies have evaluated muscle oxygenation responses during exercise. We hypothesized that lower V_ O2peak in CKD would be associated with attenuated responses in muscle oxygenation compared with those without CKD. Forty-six male Veterans [CKD stages 3 and 4, n ¼ 23; referent controls (REF), n ¼ 23] completed the study. Cardiopulmonary exercise testing was performed on a treadmill using the modified Bruce protocol. Peak change in dominant medial gastrocnemius deoxygenated hemoglobin/myoglobin fD[deoxy(Hb-Mb)]peakg, total hemoglobin/myoglobin fD[total(Hb-Mb)]peakg, tissue saturation index (DTSI), and DTSI reoxygenation half-time recovery (DTSIreoxy1/2time) were assessed via near-infrared spectroscopy (NIRS). V_ O2peak, exercise time, HRpeak, V_ O2 at gas-exchange threshold (GET), and exercise time after GET were lower in the CKD group versus the REF group (P ¼ 0.002, P textless 0.001, P ¼ 0.020, P ¼ 0.044, and P ¼ 0.005, respectively). For NIRS outcomes, D[total(Hb-Mb)]peak was lower, and DTSIreoxy1/2time prolonged, in the CKD group compared with the REF group (P ¼ 0.032 and P ¼ 0.031, respectively). V_ O2peak was positively associated with HRpeak (CKD, r ¼ 0.57, P ¼ 0.005; REF, r ¼ 0.63, P ¼ 0.001) and D[total(Hb-Mb)]peak (CKD, r ¼ 0.63, P ¼ 0.001; REF, r ¼ 0.52, P ¼ 0.012) in both groups. Conversely, V_ O2peak was positively associated with D[deoxy(Hb-Mb)]peak in the CKD group only (r ¼ 0.64, P textless 0.001). These findings suggest that skeletal muscle impairments, in addition to cardiovascular impairments, contribute to reduced V_ O2peak in patients with CKD.