Background Limited studies have suggested increased incidence rates and unusual clinical presentations of appendicitis among HIV-infected patients during the pre-highly active antiretroviral therapy (HAART) era. Data in the HAART era are sparse, and no study has evaluated potential HIV-related risk factors for the development of appendicitis. Methods We retrospectively studied 449 HIV-infected patients receiving care at a US Naval hospital involving 4750 person-years (PY) of follow-up. We also evaluated the rates of appendicitis among HIV-negative persons at our medical facility. We compared demographics, HIV-specific data, and HAART use in HIV-infected patients with and without appendicitis. Results Sixteen (3.6%) of 449 patients developed appendicitis after HIV seroconversion. The incidence rate was 337 cases/100 000 PY, more than fourfold higher than among HIV-negative persons. Eighty-eight per cent of cases among HIV-infected patients had an elevated white blood count at presentation, 39% were complicated, and 64% required hospitalization. HIV-infected patients with appendicitis compared with those who did not develop appendicitis were less likely to be receiving HAART (25 vs. 71%, P < 0.001), had higher viral loads (3.5 vs. 1.7 log(10) HIV-1 RNA copies/mL, P=0.005), and were younger (median age of 30 vs. 41 years, P < 0.002). In the multivariate model, receipt of HAART remained protective [odds ratio (OR) 0.21, P=0.012] for appendicitis, while younger age was positively associated (OR 1.08, P=0.048) with appendicitis. Conclusion Acute appendicitis occurs at higher incidence rates among HIV-infected patients compared with the general population. Our study demonstrates that the lack of HAART may be a risk factor for appendicitis among HIV-infected patients; further studies are needed.