Background. Despite the challenges facing healthcare in South Africa, empirical insights into the performance of healthcare services over time are scarce. Methods. We analysed first admissions of adult medical inpatients to Groote Schuur Hospital, Cape Town, from January 2002 to July 2009. Data included age, sex, medical specialty, and date of admission and discharge. We used population group and hospital billing codes as proxy measures for socio-economic status (SES). We calculated the duration of stay in days from the date of admission to discharge, and inpatient mortality rates per 1 000 patient days. Poisson regression was used to estimate mortality rate ratios (MRR) in unadjusted analysis and after adjusting for potential confounders. Annual increases in mortality rates were highest during the first 2 days following admission (increasing from 30.1 to 50.3 deaths per 1 000), and were associated with increasing age, non-paying patient status, black population group and male sex, and were greatest in the emergency ward (adjusted MRR 1.73, comparing 2009 with 2002; 95% CI 1.49 -2.01). Discussion. Increasing medical inpatient mortality rates at a large South African academic hospital were most marked during the first 2 days after admission and appeared greatest among emergency medical inpatients.