In the present study, we aimed to investigate the association between soluble CD40 ligand (sCD40L, a marker of platelet activation), soluble thrombomodulin, and syndecan-1 (both well-described markers of endothelial dysfunction) and metabolic syndrome in a large cohort of well-treated people with HIV (PWH) and to elucidate their association with HIV-specific variables. We included 862 PWH with undetectable viral replication. Our hypotheses were tested using uni- and multivariable logistic regression models a priori adjusted for well-known confounders. While no association of soluble thrombomodulin and syndecan-1 with MetS was found, high levels of sCD40L (aOR 1.54 [1.07–2.22]) were associated with excess risk of MetS. Given the previously described association between sCD40L, vascular inflammation and endothelial damage, the results presented in our study may suggest a potential role for sCD40L in the well-known association between cardiometabolic comorbidity and HIV infection.