Physical exercise is recommended as a treatment for unbalanced cholesterol profile. The most prominent and sustained effect of exercise on lipoproteins is increase in circulating high- density lipoprotein-cholesterol (HDL-C) and its major protein constituent apolipoprotein A1 (apoA1). Herein we used apoA1 deficient (apoA1 ko) and apoA1 human transgenic (apoA1 tg) mouse models to test hypothesis that HDL-C may modulate physical exercise capacity, training response, and energy homeostasis. Male apoA1 ko mice have severely reduced and apoA1 tg mice have markedly increased HDL-C levels compared to wild type (wt) mice. In addition, levels of circulating triglycerides and neutral fatty acids are increased in ApoA1 tg mice and triglycerides reduced in ApoA1 ko mice compared to wt mice. ApoA1 ko mice have lower body weight than other genotypes while response to glucose tolerance test was improved in ApoA1 tg mice. Mice were divided to sedentary and training (tread mill running 5 d/week, 1 h/d) groups. After 4 weeks of training, bodyweight and fat mass of training mice had decreased and their performance in exercise endurance test was better than their sedentary littermates. The distance covered by trained apoA1 ko mice during endurance test was significantly shorter compared to the distance covered by trained apoA1 tg mice and similar trend was observed with sedentary mice. We conclude that ApoA1 levels have an effect on the amount of circulating energy substrates and their absorption. Increased levels of HDL-C enhance glucose homeostasis and these observations together may have an effect on exercise recovery and adaptation as well as availability of energy substrates during exercise. Results of this study also suggest that low levels of HDL-C reduce exercise endurance capacity.