Many questions remain unanswered regarding the epidemiology, pathophysiology, diagnosis, treatment, and monitoring of Trypanosoma cruzi infection in people with HIV (PWH). The reported prevalence of T. cruzi infection in PWH living in endemic countries ranges from 1–28% and is likely similar in at-risk US populations. While classic cardiac and gastrointestinal presentations of chronic Chagas disease occur in PWH, PWH are additionally at risk for a severe and often fatal form of T. cruzi-mediated disease called reactivation disease. T. cruzi reactivation typically occurs in PWH with low CD4 counts and poor virologic control. National HIV guidelines in several endemic South American countries recommend that all PWH be screened for T. cruzi infection at the time of HIV diagnosis; however, this recommendation is not widely implemented. The early detection of T. cruzi infection in PWH is critical as the sequelae of Chagas disease, including T. cruzi reactivation, may be preventable through the restoration of robust cellular immunity via the initiation of antiretroviral therapy and the appropriate use of antitrypanosomal therapy.