The purpose of this study was to assess if there exists an association between C34T muscle adenosine monophosphate deaminase ( AMPD1) genotypes (i.e., normal homyzygotes [CC] vs. heterozygotes [ CT]) and directly measured indices of exercise capacity (peak oxygen uptake [VO(2peak)], ventilatory threshold [VT], gross mechanical efficiency [GE], etc.) in 44 Caucasian McArdle patients (23 males, 21 females). All patients performed a graded cycle ergometer test until exhaustion (for VO(2peak) and VT determination) and a 12-min constant-load test at the power output eliciting the VT (for GE determination). We found no significant difference in indices of exercise capacity between CC (n = 18) and CT genotypes (n = 5) in the group of male patients (p > 0.05). In contrast, the VO(2) at the VT was significantly lower (p < 0.05) in CT (n = 4; 7.9 +/- 0.4 ml/kg/min) than in CC female patients (n = 17; 11.0 +/- 0.9 ml/kg/min). In summary, heterozigosity for the C34T allele of the AMPD gene is associated with reduced submaximal aerobic capacity in female patients with McArdle disease and might partly account, in this gender, for the variability that exists in the phenotypic manifestation of the disease.