Background/ObjectivesTo evaluate the impact of maximal fat oxidation intensity exercise combined with calorie restriction intervention on lipid-related parameters in a hypercholesterolemic population, and to determine if an optimal range of calorie restriction exists for effectively enhancing blood lipid profiles.MethodsA 4-week intervention study combined exercise and calorie restriction for 64 patients aged 18–60 with secondary hypercholesterolemia. Ultimately, 43 participants completed the study. The dietary intervention adhered to the principles of a balanced diet, with meal plans designed to provide three meals per day for the duration of the study. Each subject’s daily calorie intake was set to match their individual resting energy expenditure (REE) plus varying proportions of physical activity (PA) calories. Participants were divided into four groups based on these proportions: REE only, REE + PA33%, REE + PA67%, and REE + PA100%. FATmax exercises were conducted 5 times per week, lasting 1 h each.Results1) Compared with baseline, subjects’ body weight, fat mass and body fat rate decreased significantly; fat-free mass also decreased significantly in the REE, REE + PA33%, and REE + PA67% groups. 2) Subjects’ serum TC decreased significantly; serum LDL-C and ApoB decreased significantly in the REE, REE + PA33%, and REE + PA67% groups; there were no significant changes in serum HDL-C and ApoA1. 3) Serum PCSK9 was significantly decreased in the REE and the REE + PA 67% groups; serum LDLR was significantly decreased in all groups of subjects. 4) Between the groups, the rate of change in serum LDL-C was significantly different.ConclusionFATmax exercise combined with proper proportions of calorie restriction can significantly decrease serum cholesterol levels and fat mass in hypercholesterolemic patients. Nevertheless, it is misleading to assume that a drastic reduction in calorie intake invariably results in superior outcomes. Optimal cost-effectiveness may be achieved within a calorie restriction range of REE + PA33-67%.