Men with human immunodeficiency virus (HIV) infection are often hypogonadal and develop several HIV-associated non-acquired immunodeficiency syndrome (AIDS) (HANA) conditions that impair overall health status. No studies explored the relationship between health status and serum testosterone (T) in HIV-infected men. This study aims to investigate the association between total serum T and HANA, multimorbidity, and frailty in a large cohort of 1359 HIV-infected men and to explore the relationship between patients' overall health status and serum T. Among biochemical and hormonal measurement performed the main are serum total T, free triiodothyronine (fT3), and luteinizing hormone. Other outcome measurements include anthropometry, assessment of comorbidities and disabilities, overall health status defined as the number of HANA and by the 38-item multimorbidity frailty index, anthropometry, and bone mineral density. The cumulative relative risk of comorbidities is increased in HIV-infected men with hypogonadism (p<0.001) and hypogonadism is associated with several comorbidities. The prevalence of hypogonadism increases progressively with the increase of the number of comorbidities. Frailty index is inversely related to serum total T (age-adjusted r=0.298, r(2)=0.089, p<0.0001). Serum fT3 levels are significantly lower in hypogonadal than eugonadal men (p=0.022). This suggests that low serum T could be considered a sensitive marker of frailty and poor health status and that the latter might induce hypogonadism. The more HIV-infected men are frail the more they are hypogonadal. This suggests that hypogonadism might be a naturally occurring condition in unhealthy HIV-infected men and raises concern about the safety of T treatment. In conclusion, low serum T is associated with multimorbidity, HANA, and frailty in HIV-infected men and this association seems to be bidirectional. Given the wide attitude to offer T treatment to HIV-infected men, caution is needed when prescribing T to HIV-infected male patients, especially if the patient is unhealthy or frail.