It is estimated that infertility affects approximately 15% of couples of reproductive age in Western countries, and in up to 50% of these cases, a male infertility-associated factor (MFI) can be recognized. Fertility and somatic health share a complex and dynamic relationship. Several efforts have been made to identify pathobiology mechanisms supporting the association between poor semen parameters, male infertility, and medical conditions including oncologic, cardiovascular, autoimmune, and other chronic diseases. Concerning data showed an association between male infertility and increased mortality, largely attributed to these chronic comorbidities. The importance of disentangling this relationship relies on the possibility of revealing novel therapeutic options for infertility. As well, it is important to implement ad hoc screening programs in infertile men for specific comorbidities and to improve physical and psychological health of infertile men. Based on these findings, it emerges how assessing comprehensive health status of the patient is of primary importance in the MFI setting. Data also suggest that impaired semen parameters may predict mortality, supporting the notion that semen analysis could represent a potential biomarker of overall health and fitness.