To describe changes in prevalence of hypertension, diabetes, HIV and tuberculosis, and prevalence of comorbidity, and to investigate associations between each condition, and combinations of conditions, with self-reported general health and hospital admission. This study used data from a longitudinal population-based HIV and health surveillance cohort, conducted by the Africa Health Research Institute in Umkhanyakude district of rural KwaZulu-Natal, South Africa. Prevalence of hypertension, HIV and diabetes increased from 2009 to 2015, and prevalence of tuberculosis decreased. 81% of the 47 334 participants were female; hypertension and diabetes were the commonest conditions in people over age 50, whereas HIV was most common in those younger than 50 years. Comorbidity of communicable and non-communicable conditions was commonest in 40- to 60-year-olds. The adjusted odd ratios (OR) for better self-reported general health with multimorbidity were 0.53 (95% CI 0.51-0.56), 0.29 (95% CI 0.27-0.29), 0.25 (95% CI 0.21-0.37) and 0.21 (95% CI 0.12-0.37) for one, two, three and four conditions, respectively, vs. no conditions. Tuberculosis was most strongly and inversely associated with better general health (OR 0.34 (0.31-0.37) and most strongly associated with hospital admission (OR 3.26 (2.32-2.99)). The high prevalence of communicable and non-communicable conditions in this rural South African population is giving rise to a burden of multimorbidity, as increased access to antiretroviral treatment has reduced mortality in people with HIV. Healthcare systems must adapt by working towards integrated primary care for HIV/AIDS and non-communicable diseases.