BackgroundIncreasing unsaturated fat intake is beneficial for cardiovascular health, but the type of unsaturated fat to recommend remains equivocal. ObjectivesWe investigated the effects of an 8-week diet intervention that was rich in either cottonseed oil (CSO; PUFA rich) or olive oil (OO; MUFA rich) on blood lipids in hypercholesterolemic adults. MethodsForty-three men and women with hypercholesterolemia (53 ± 10 years; BMI, 27.6 ± 4.8 kg/m2) completed this randomized parallel clinical trial consisting of an 8-week partial outpatient feeding intervention. Participants were given meals and snacks accounting for ∼60% of their daily energy needs, with 30% of energy needs from either CSO (n = 21) or OO (n = 22). At pre- and postdiet intervention visits, participants consumed a high-SFA meal (35% of total energy needs; 70% of energy from fat). The primary outcomes of fasting cholesterol profiles and secondary outcomes of postprandial blood lipids and glycemic markers were assessed over a 5-hour period. ResultsThere were greater reductions from baseline to week 8 in fasting serum total cholesterol (TC; −17.0 ± 3.94 mg/dL compared with −2.18 ± 3.72 mg/dL, respectively; P = 0.008), LDL cholesterol (−19.7 ± 3.94 mg/dL compared with −5.72 ± 4.23 mg/dL, respectively; P = 0.018), non–HDL cholesterol (−20.8 mg/dL ± 4.00 compared with −6.61 ± 4.01 mg/dL, respectively; P = 0.014), and apoB (−11.8 mg/dL ± 2.37 compared with −3.10 ± 2.99 mg/dL, respectively; P = 0.05), in CSO compared with OO. There were also visit effects from baseline to week 8 for increases in HDL cholesterol (CSO, 56.5 ± 2.79 mg/dL to 60.2 ± 3.35 mg/dL, respectively; OO: 59.7 ± 2.63 mg/dL to 64.1 ± 2.24 mg/dL, respectively; P < 0.001), and decreases in the TC:HDL-cholesterol ratio (CSO, 4.30 ± 0.27 mg/dL to 3.78 ± 0.27 mg/dL, respectively; OO, 3.94 ± 0.16 mg/dL to 3.57 ± 0.11 mg/dL, respectively; P < 0.001), regardless of group assignment. In response to the high-SFA meal, there were differences in postprandial plasma glucose (P = 0.003) and triglyceride (P = 0.004) responses and a trend in nonesterified fatty acids (P = 0.11) between groups, showing protection in the postprandial state from an occasional high-SFA fat meal with CSO, but not OO, diet enrichment. ConclusionsCSO, but not OO, diet enrichment caused substantial improvements in fasting and postprandial blood lipids and postprandial glycemia in hypercholesterolemic adults. This trial was registered at clinicaltrials.gov as NCT04397055.