Background No African countries were included in the development of the Simplified Acute Physiology Score 3 (SAPS 3). This study aimed to assess the performance of the SAPS 3 as a predictor of hospital mortality in patients admitted to a multidisciplinary tertiary intensive care unit (ICU) in South Africa. Methods A prospective cohort study was undertaken in a tertiary single-centre closed multidisciplinary ICU with 16 beds over 12 months in 2017. First time admissions 12 years and over were included. Exclusions were patients who died within six hours of admission, incomplete data sets and unknown outcome after ICU discharge. Demographic data, clinical admission data and co-morbidities were recorded. The SAPS 3 score was calculated within the first hour of ICU admission. The highest Sequential Organ Failure Assessment score, vasopressor use, mechanical ventilation requirements and details of acute kidney injury, if present, were recorded. Discrimination of the model was evaluated using an area under the receiver operating characteristic curve (AUROC) and calibration by the Hosmer-Lemeshow (HL) Goodness of Fit Test (Ĉ and Ĥ statistic). The observed versus the SAPS 3 model predicted mortality ratios were compared and the standardized mortality ratio (SMR) was calculated. Results A total of 829 admissions with a mean SAPS 3 (SD) of 48.1 (16) were included. Of patients with a known human immunodeficiency virus (HIV) status, 32,4% were positive. The ICU and hospital mortality rates were 13.3% and 21.4% respectively. The SAPS 3 model had a AUROC of 0.796 and HLĈ and Ĥ statistics were 12.1 and 11.8 (p-values 0.15 and 0.16).