In various cross-sectional and longitudinal studies, exercise has been associated with cardiometabolic outcomes, including high-density lipoprotein (HDL) cholesterol. Exercise-induced changes in HDL cholesterol seem to be affected by genetic polymorphisms. In this study, we examined whether variantAPOErs7412 is involved in the association between HDL cholesterol and exercise. From adults assessed in Taiwan Biobank (TWB) between 2008 and 2019, we analyzed data from 57,638 normolipidemic subjects. To examine the association between exercise,APOErs7412, and HDL cholesterol, a multiple linear regression model was used. A higher HDL was associated with both aerobic exercise (regression coefficient [mg/dL] beta- (β), 1.112; 95% confidence interval (CI); 0.903–1.322) and resistance exercise (β, 2.530; 95% CI, 2.093–2.966). In comparison with theAPOErs7412-CC genotype, the β was 2.589 (95% CI, 2.329–2.848) among those with the CT + TT genotype. Compared to adults who had the CC genotype and did not exercise (the CC/no exercise group), the β-coefficient determined for the different genotype and exercise groups was 1.135 (95% CI, 0.911–1.359) for the CC genotype and aerobic exercise group, 2.753 (95% CI, 2.283–3.322) for the CC genotype and resistance exercise group, 2.705 (95% CI, 2.390–3.020) for the CT + TT genotype and no exercise group, 3.682 (95% CI, 3.218–4.146) for the CT + TT genotype and aerobic exercise group, and 3.855 (95% CI, 2.727–4.982) for the CT + TT genotype and resistance exercise group, respectively. This study demonstrates that self-reported aerobic and resistance exercise both raised HDL levels, yet resistance exercise was associated with a greater increase, particularly among Taiwanese subjects carrying theAPOErs7412-CT+TT genotype.