Introduction of antiretroviral therapy (ART) has dramatically reduced the incidence of infectious ocular diseases in human immunodeficiency virus (HIV)-infected individuals. However, the effects of long-term ART and chronic HIV infection on the eye are ill-defined. This study determined the occurrence and severity of ocular diseases among 342 participants in a rural South African setting: HIV-naïve (n = 105), HIV-infected ART-naïve (n = 16), HIV-infected on ART for <12 months (short-term ART; n = 56) and HIV-infected individuals on ART for >36 months (long-term ART; n = 165). More HIV-infected participants presented with an external eye condition, in particular blepharitis, than HIV-naïve individuals (18% vs. 7%; age-adjusted odds ratio (aOR) = 2·8, P < 0·05). Anterior segment conditions (particularly keratoconjunctivitis sicca and pterygium) were also more common (50% vs. 27%; aOR = 2·4; P < 0·01). Compared with individuals on short-term ART, participants receiving long-term ART were more likely to have clinically detectable cataract (57% vs. 38%; aOR = 2·2, P = 0·01) and posterior segment diseases, especially HIV retinopathy (30% vs. 11%; aOR = 3·4, P < 0·05). Finally, long-term ART was significantly associated with presence of HIV retinopathy (P < 0·01). These data implicate that ocular disease is more common and of more diverse etiology among HIV-infected individuals, especially those on long-term ART and suggest that regular ophthalmological monitoring of HIV-infected individuals on ART is warranted.