Background Despite improved availability and better access to antiretroviral therapy (ART), approximately 36% of human immunodeficiency virus (HIV)-positive South Africans are still not virally suppressed. Objective The aim of this study was to describe the patterns of presentation of HIV-positive patients to a major central hospital emergency department (ED). Methods In this prospectively designed study, consecutive HIV-positive patients presenting to the Charlotte Maxeke Johannesburg Academic Hospital (CMJAH) adult ED were enrolled between 07 July 2017 and 18 October 2018. Results A total of 1224 participants were enrolled. Human immunodeficiency virus was newly diagnosed in 212 (17.3%) patients, 761 (75.2%) were on ART, 245 (32.2%) reported ART non-adherence, 276 (22.5%) had bacterial pneumonia, 244 (19.9%) had tuberculosis (TB), 86 (7.0%) had gastroenteritis, 205 (16.7%) required intensive care unit admission, 381 (31.1%) were admitted for ≥ 7 days and 166 (13.6%) died. With regard to laboratory parameters, CD4 cell count was < 100 cell/mm3 in 527 (47.6%) patients, the viral load (VL) was > 1000 copies/mL in 619 (59.0%), haemoglobin was < 11 g/dL in 636 (56.3%), creatinine was > 120 µmol/L in 294 (29.3%), lactate was > 2 mmol/L in 470 (42.0%) and albumin was < 35 g/L in 633 (60.8%). Conclusion Human immunodeficiency virus-positive patients presenting to the CMJAH ED demonstrated a high prevalence of opportunistic infections, required a prolonged hospital stay and had high mortality rates. There is a need to improve the quality of ART services and accessibility to care.