Palm oil (PO) may be an unhealthy fat because of its high saturated fatty acid content. The objective was to assess the effect of substituting PO for other primary dietary fats on blood lipid-related markers of coronary heart disease (CHD) and cardiovascular disease (CVD). We performed a systematic review and meta-analysis of dietary intervention trials. Studies were eligible if they included original data comparing PO-rich diets with other fat-rich diets and analyzed at least one of the following CHD/CVD biomarkers: total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, TC/HDL cholesterol, LDL cholesterol/HDL cholesterol, triacylglycerols, apolipoprotein A-I and B, very-low-density lipoprotein cholesterol, and lipoprotein(a). Fifty-one studies were included. Intervention times ranged from 2 to 16 wk, and different fat substitutions ranged from 4% to 43%. Comparison of PO diets with diets rich in stearic acid, monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs) showed significantly higher TC, LDL cholesterol, apolipoprotein B, HDL cholesterol, and apolipoprotein A-I, whereas most of the same biomarkers were significantly lower when compared with diets rich in myristic/lauric acid. Comparison of PO-rich diets with diets rich in trans fatty acids showed significantly higher concentrations of HDL cholesterol and apolipoprotein A-I and significantly lower apolipoprotein B, triacylglycerols, and TC/HDL cholesterol. Stratified and meta-regression analyses showed that the higher concentrations of TC and LDL cholesterol, when PO was substituted for MUFAs and PUFAs, were not significant in young people and in subjects with diets with a lower percentage of energy from fat. Both favorable and unfavorable changes in CHD/CVD risk markers occurred when PO was substituted for the primary dietary fats, whereas only favorable changes occurred when PO was substituted for trans fatty acids. Additional studies are needed to provide guidance for policymaking.