Introduction: To investigate the prevalence and spectrum of comorbidities in South Africans with systemic lupus erythematosus (SLE). Patients and methods: A nested case-control study of a known alive group (AG) and deceased group (DG) of 200 and 40 patients, respectively, matched for age and sex, attending a tertiary Lupus Clinic. Comorbidities that were documented included, but not restricted to, those listed in the Charlson comorbidity index (CCI). Lupus disease severity was assessed using the lupus severity index (LSI). Results: Patients were mainly black female (94%), and the median age (IQR) and median disease duration (IQR) were 33 (25–42) and 6 (3–11) years, respectively. Overall, 191 (79.5%) patients experienced ≥ 1 comorbidities. The median (IQR) LSI and CCI scores were significantly higher in the DG than the AG (8.5 (6.7–9.1) vs 6.3 (5.2–8.3), p < 0.001 and 1 (1–3) vs 0 (0–2), p = 0.002, respectively). The commonest comorbidities were hypertension (42%), serious infections (36.6%) and tuberculosis (TB) (18.8%), the latter two being significantly more common in the DG (OR = 7.34, p < 0.0001 and OR = 3.40, p = 0.001, respectively). Of the CCI comorbidities, congestive cardiac failure (OR = 10.39, p = 0.0003), cerebrovascular disease (OR = 7.29, p = 0.01) and chronic kidney disease (OR = 3.08, p = 0.02) were more common in the DG. Both serious infections and TB were independent predictors of death. Conclusion: In this study of predominantly black South African SLE patients, comorbidities were common, with serious infections and TB amongst the commonest comorbidities. Unlike in industrialised Caucasian populations, cardiovascular comorbidities were rare in spite of a high prevalence of HPT. [ABSTRACT FROM AUTHOR]