This study investigates whether there are major gene effects on oxygen uptake at the ventilatory threshold (VO(2VT)) and the VO(2VT) maximal oxygen uptake (VT%VO(2 max)), at baseline and in response to 20 wk of exercise training by using data on 336 whites and 160 blacks. Segregation analysis was performed on the residuals of VO(2VT) and VT%VO(2 max). In whites, there was strong evidence of a major gene, with 3 and 2% of the sample in the upper distribution, that accounted for 52 and 43% of the variance in baseline VO(2VT) and VT%VO(2 max), respectively. There were no genotype-specific covariate effects (sex, age, weight, fat mass, and fat-free mass). The segregation results were inconclusive for the training response in whites, and for the baseline and training response in blacks, probably due to insufficient power because of reduced sample sizes or smaller gene effect or both. The strength of the genetic evidence for VO(2VT) and VT%VO(2 max) suggests that these traits should be further investigated for potential relations with specific candidate genes, if they can be identified, and explored through a genome-wide scan.