In hypertriglyceridemic (HTG) patients the addition of fish oil to the diet causes a marked reduction in the concentration of triglyceride-rich lipoproteins in the serum. To investigate the effects of fish oil on the oxidation resistance of VLDL and LDL in HTG patients, nine male patients received 1 g/d fish oil (containing 55.7% n-3 polyunsaturated fatty acids [PUFAs] and 1 U α-tocopherol/g fish oil) for 6 weeks followed by 5 g/d fish oil for an additional 6 weeks. Cu2+ -induced oxidation of VLDL and LDL was measured by continuous monitoring of conjugated dienes. Supplementation with 1 g/d fish oil caused hardly any changes in the n-3 PUFA content of lipoproteins or lipoprotein concentrations in serum. However, supplementation with 5 g/d fish oil resulted in a significant increase of n-3 PUFA content in VLDL (from 2.5% to 6.4% of total fatty acids) and LDL (from 3.2% to 6.4% of total fatty acids), decreases in serum triglyceride, VLDL triglyceride, and VLDL cholesterol concentrations of 54%, 56%, and 40%, respectively, and an increase in LDL Cholesterol of 23%. The lag times of VLDL and LDL oxidation decreased from 197 to 140 minutes (-29%)and 101 to 86 minutes (-15%), respectively. At the end of the 5 g/d fish oil supplementation the lag times of VLDL and LDL oxidation were correlated with their respective n-3 PUFA content (r= -.67; P<.05 and r = -.79; P<.02, respectively). Before and at the end of supplementation with 5 g/d fish oil the lag times and propagation tales of VLDL oxidation also correlated with the total number of double bonds in all PUFAs of VLDL. We conclude that fish oil supplementation strongly reduces serum concentrations of total triglycerides, VLDL triglycerides, and VLDL cholesterol. However, in HTG patients fish oil supplementation increased the serum LDL cholesterol concentration and the susceptibility of VLDL and LDL to oxidation.