PURPOSE: To find new non-invasive methods for functional evaluation of patients with metabolic myopathies during exercise. METHODS: Two patients with defects of respiratory chain enzymes (complex III in patient A and complex IV in patient B) and two patients with myophosphorylase deficiency (McArdle's disease) (patients C and D) underwent several repetitions of a constant submaximal load and an incremental exercise to exhaustion on a cycloergometer. Breath-by-breath pulmonary O2 uptake (VO2), heart rate (HR) and vastus lateralis muscle oxygenation indices (by Near Infrared Spectroscopy, NIRS) were determined continuously. The VO2 kinetics was evaluated during the transition from unloaded pedaling to the constant-load test. RESULTS: The following results were obtained, respectively, in the 4 patients (A, B, C, D): peak VO2 14.4, 15.9, 10.4, 16.4 ml/kg/min (vs. 25–45 in controls); peak HR (as a percentage of the age-predicted peak HR) 90, 90, 86, 99%; mean response times of the VO2 kinetics 81, 133, 80, 100 s (vs. 35–45 in controls). The slower than normal VO2 kinetics should contribute to the reduced exercise tolerance of these patients. Changes in deoxygenated hemoglobin concentration (Δ[HHb]) in the vastus lateralis at exhaustion, expressed as a percentage of the Δ[HHb] changes observed during limb ischemia, were 3, 5, 8, 12% (vs. 78 ± 11% in controls), indicating a profound inability by the patients' skeletal muscle to increase O2 extraction during exercise. CONCLUSION: In patients with defects of respiratory chain or glycolytic enzymes, analysis of pulmonary VO2 kinetics and muscle oxygenation indices by NIRS could represent useful tools for functional evaluation. (Supported in part by Thelethon Italy Grant n. 1161C)