Although vegan diets have been reported to be associated with a reduced risk of cardiovascular disease, it was not known whether this might be partly due to vegan diets’ effects on plasma triglyceride metabolism. This study aimed to investigate if there are differences in the activity of lipoprotein lipase (LPL), an enzyme that functions at the vascular endothelium and is responsible for triglyceride breakdown, in sera obtained from vegans and omnivores. LPL activity was assessed using isothermal titration calorimetry, which allows measurements in undiluted serum samples, mimicking physiological conditions. Fasted sera from 31 healthy participants (12F 2M vegans, 11F 6M omnivores) were analyzed. The results indicated no significant differences in average LPL activity between the vegan and omnivore groups. Interestingly, despite similar triglyceride levels, there were considerable variations in LPL activity and total very-low-density lipoprotein triglyceride breakdowns between individuals within both groups. Biomarker analysis showed that vegans had lower total cholesterol and LDL-C levels compared to omnivores. These findings suggest that the lipid-related benefits of a vegan diet, in terms of atherogenic risk, may primarily stem from cholesterol reduction rather than affecting serum as a medium for LPL-mediated triglyceride breakdown. In healthy individuals, lipid-related changes in serum composition in response to a vegan diet are likely overshadowed by genetic or other lifestyle factors.