In South Africa, the Coronavirus Disease 2019 (COVID-19) pandemic is occurring against the backdrop of high Human Immunodeficiency Virus (HIV), tuberculosis and non-communicable disease burdens as well as prevalent herpesviruses infections such as Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV). As part of an observational study of adults admitted to Groote Schuur Hospital, Cape Town, South Africa during the period June–August 2020 and assessed for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, we measured KSHV serology and KSHV and EBV viral load (VL) in peripheral blood in relation to COVID-19 severity and outcome. A total of 104 patients with PCR-confirmed SARS-CoV-2 infection were included in this study. 61% were men and 39% women with a median age of 53 years (range 21–86). 29.8% (95% CI: 21.7–39.1%) of the cohort was HIV positive and 41.1% (95% CI: 31.6–51.1%) were KSHV seropositive. EBV VL was detectable in 84.4% (95% CI: 76.1–84.4%) of the cohort while KSHV DNA was detected in 20.6% (95% CI: 13.6–29.2%), with dual EBV/KSHV infection in 17.7% (95% CI: 11.1–26.2%). On enrollment, 48 [46.2% (95% CI: 36.8–55.7%)] COVID-19 patients were classified as severe on the WHO ordinal scale reflecting oxygen therapy and supportive care requirements and 30 of these patients [28.8% (95% CI: 20.8–38.0%)] later died. In COVID-19 patients, detectable KSHV VL was associated with death after adjusting for age, sex, HIV status and detectable EBV VL [p = 0.036, adjusted OR = 3.17 (95% CI: 1.08–9.32)]. Furthermore, in HIV negative COVID-19 patients, there was a trend indicating that KSHV VL may be related to COVID-19 disease severity [p = 0.054, unstandardized co-efficient 0.86 (95% CI: –0.015–1.74)] in addition to death [p = 0.008, adjusted OR = 7.34 (95% CI: 1.69–31.49)]. While the design of our study cannot distinguish if disease synergy exists between COVID-19 and KSHV nor if either viral infection is indeed fueling the other, these data point to a potential contribution of KSHV infection to COVID-19 outcome, or SARS-CoV-2 infection to KSHV reactivation, particularly in the South African context of high disease burden, that warrants further investigation