Objectives: It is much debated whether the MS contributes additional information over and above that provided by the individual components of the syndrome alone. Amongst HIV-infected individuals, we investigated whether any particular combinations of the components of the MS definition are associated with a higher risk of CVD. Research Design and Methods: We followed 33,347 HIV-infected individuals in a prospective observational study. The effect of combinations of components of the MS (low HDL cholesterol, high triglycerides, high BMI, hypertension and diabetes mellitus) on the risk CVD was assessed by Poisson regression incorporating interactions between each component pair and adjusting for age, sex, family history of CVD, smoking status, calendar year and exposure to antiretroviral therapy. We reduced the risk of type 1 errors by randomly splitting the dataset for training (70% of sample) and validation (remaining 30%). Results: In the training dataset, 671 patients experienced a CVD event over 110,652 person-years. Unadjusted, MS at study enrolment (>/=3 of the factors) was associated with a 2.89 higher risk of CVD (95% confidence interval [CI] 2.34, 3.59; p=0.0001) compared with individuals without the MS. After adjustment for the individual components, the MS as an entity no longer predicted the risk of CVD (adjusted relative risk 0.85; 95% CI 0.61, 1.17; p=0.32). No significant positive interactions were found between the components of the MS. Conclusions: The presence of the MS in HIV-infected individuals did not appear to increase the CVD risk over and above that conferred by the components of the syndrome separately.