The relationship between extramarital affairs and cardiovascular risk is still not completely clarified. The aim of this study was to investigate whether extramarital affairs have a protective effect on cardiovascular risk or, conversely, a deleterious one. Among patients studied, 91.8% of the whole sample reported no or occasional extramarital affairs, while 8.2% declared a stable secondary relationship. During a median follow-up of 4 [0–8] years, 95 major adverse cardiovascular events (MACE), eight of which were fatal, were observed. Cox analysis, after adjustment for confounding factors, showed that presence of stable extramarital affair was associated with a higher incidence of MACE (HR = 2.13 [1.12; 4.07], p = 0.023). The introduction in the Cox model of patient perceived partner’s hypoactive sexual desire (PPPHSD) attenuates the association (HR 1.86 [0.93; 3.70], p = 0.078). The sample was therefore divided according to PPPHSD. We observed that unadjusted incidence of MACE was significantly associated with presence of extramarital affairs only in men reporting a primal partner without PPPHSD. This association was also confirmed in a Cox regression model, after adjusting for confounders (HR = 2.87 [1.81; 6.98], p = 0.020). We can conclude that to be unfaithful represents an independent risk factor for MACE. Therefore, infidelity induces not only heart trouble in the betrayed partners, but seems to be also able to increase the betrayer’s heart-related events.