This systematic review and meta-analysis of clinical trials assess the effects of fructose epimers on blood lipids, including high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG) and free fatty acids (FFA). PUBMED, EMBASE, Cochrane Library and Web of science databases were retrieved up to March 2023. A total of 11 trials including 640 participants were eligible, although all the trials were not at low risk of bias. Data were pooled with weighted mean differences (WMD). The combined data revealed that single dose D-allulose intervention notably increased postprandial FFA levels (WMD=0.11 mEq/L; 95% CI, 0.07 to 0.12; P < 0.001) but no significant effect on postprandial TG, TC, LDL-C and HDL-C. Daily intervention of D-allulose significantly amplified fasting TC (WMD=6.81 mg/dL; 95% CI, 0.25 to 13.37; P = 0.042), LDL-C (WMD=7.42 mg/dL; 95% CI, 1.73 to 13.12; P = 0.011) and FFA (WMD=0.03 mEq/L; 95% CI, 0.01 to 0.04; P = 0.002). D-tagatose showed no significant effect on fasting or postprandial lipid profiles. These results implied that fructose epimers intake elicited a modest impairment in blood lipid homeostasis. Nonetheless, additional long-term randomized controlled trials with stronger designs are necessary to reiterate and maintain the validity of these effects.