ABSTRACT Background: Prognostic nutritional index (PNI) and systemic immune-inflammatory index (SII) are two novel markers that have emerged as potential candidates as an early indication of the severity of the disease in coronavirus disease 2019 (COVID-19) patients. Objective: The objective of the study is to assess the utility of the prognostic nutritional index (PNI) and systemic immune-inflammatory index (SII) as markers of severity among patients with COVID-19 infection. Methods: This is a retrospective study conducted in a tertiary care centre in South India. A total of 80 patients diagnosed with COVID-19 were included in the study. The patients were divided into mild, moderate, and severe groups based on the clinical parameters as per Indian Council of Medical Research guidelines. Lab values taken at admission were obtained from patient records, using which the PNI and SII were calculated using standard formulae. These markers were correlated with the severity of the COVID-19 illness. Results: PNI and SII were significantly elevated in the patients with severe COVID-19 illness as compared with mild COVID-19 illness. The mean PNI among subjects with mild COVID-19 and severe COVID-19 being 46.62 ± 6.51 and 34.09 ± 5.81, respectively. The mean SII among subjects with mild COVID-19 was 9,52,287.2 ± 1,42,113, and among subjects with severe COVID-19 was 15,39,461 ± 8,04,285. The cut-off value for PNI and SII for predicting severity of COVID-19 illness was 35.93 and 5,82,400, respectively. The sensitivity for PNI was 87.5, and the SII was 95. Conclusion: The present study showed a significant correlation between the SII and PNI as markers used to determine the severity of COVID-19. Based on these findings, it can be effectively used independently of other markers to predict critical illness among COVID-19 patients.