The purpose of this study was to examine the relationship between the α2 (exon 1 and exon 21-22 with BglII) and β1 (MspI and PvuII) genes of the sodium potassium adenosine triphosphatase and resting metabolic rate (RMR) and respiratory quotient (RQ). The sample included 582 participants from 171 families of the Quebec Family Study. RMR and RQ were adjusted for age, sex, fat mass, and fat free mass. Sib-pair analyses indicated a significant linkage between RQ and the α2 exon 1 marker (P = 0.03) and the α2 exon 21-22 marker (P = 0.02). No linkage was detected between the β1 markers and either RMR or RQ, whereas RMR was not linked with the α2 makers. There was a significant interaction (P < 0.0003) between α2 exon 1 carrier status and age group [younger (<45 yr) vs. older (≥45 yr) adults] for RQ. The association between carrier status and RQ was significant in younger adults (RQ = 0.76 in carriers vs. 0.80 in non-carriers, P < 0.0001) but was not in older adults (RQ = 0.81 in carriers vs. 0.80 in noncarriers). The α2 exon 1 gene accounted for approximately 9.1% and 0.3% of the variance in RQ in younger and older adults, respectively. The results suggest that the sodium potassium adenosine triphosphatase α2 gene may play a role in fuel oxidation, particularly in younger individuals.