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Many questions remain unanswered regarding the epidemiology, pathophysiology, diagnosis, treatment, and monitoring of <i>Trypanosoma cruzi</i> infection in people with HIV (PWH). The reported prevalence of <i>T. cruzi</i> 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 <i>T. cruzi</i>-mediated disease called reactivation disease. <i>T. cruzi</i> 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 <i>T. cruzi</i> infection at the time of HIV diagnosis; however, this recommendation is not widely implemented. The early detection of <i>T. cruzi</i> infection in PWH is critical as the sequelae of Chagas disease, including <i>T. cruzi</i> reactivation, may be preventable through the restoration of robust cellular immunity via the initiation of antiretroviral therapy and the appropriate use of antitrypanosomal therapy.