Background Narrative descriptions of HIV and Trypanosoma cruzi, the causative agent of Chagas disease, co-infection exist in the literature but the breadth and depth of the data underlying these descriptions has not been previously thoroughly scrutinised and reactivation is poorly understood. The aim of this systematic review was to identify, synthesise and analyse the published literature on the epidemiology and clinical features of T. cruzi and HIV co-infection. Methods A systematic review of published literature on HIV and T. cruzi co-infection was conducted. Six international databases were searched: Medline, Embase, Global Health, Global Index Medicus, Web of Science and Scopus. Articles reporting on HIV and T. cruzi co-infection, as defined by the authors, with no restrictions on study type, language or date of publication or reporting were included. Results 152 articles (62% case reports or series) were included which reported on 1,603 individuals with co-infection and 225 with presumed reactivation. Reported prevalence of co-infection varied greatly by region and setting of screening, from 0.1 to 1% in unselected populations, and was particularly high when screening inpatients known to have HIV for T. cruzi infection (26-48%). 83% of reactivations were reported in individuals with CD4<200 cells/mm3. CNS reactivation, typically presenting with meningoencephalitis and/or cerebral lesions, accounted for 68% of all published cases of reactivation. Myocarditis (accounting for 9% published reactivation cases) was less well characterised. Mortality of all reactivation cases was 59% (77% in those with CNS reactivation). Conclusion T. cruzi reactivation mainly affects those with untreated HIV and lower CD4 counts. CNS reactivation is the most common clinical picture and confers high mortality. Prompt recognition of reactivation and immediate initiation of trypanocidal therapy (with benznidazole or nifurtimox) is recommended. Increased education and better awareness of the risks of co-infection are needed, as is systematic screening of individuals at-risk.