question: Background: The COVID-19 pandemic has resurfaced in India in the form of a hard-hitting second wave. This study aims to compare the clinical profile of the first wave (April-June 2020) and the second wave (March-May 2021) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a single tertiary care center of India. This will help prioritize the target population group and management strategies in the upcoming third wave if any. Methods: In this retrospective observational study, we examined the demographic profile, symptoms at presentation, the severity of illness, baseline investigations, treatments received, underlying comorbidities, and outcomes of the COVID-19 patients belonging to the first (W1) and the second wave (W2) of the pandemic in India. Findings: The age group affected most in the W2 is 50.5 (SD=17.7) years compared with 37·1 (SD=16·9) years for the W1. The baseline oxygen saturation is lower in W2, being 84·0 (13·4) % compared with 91·9 (7·4) % in W1. 70.2 % of the cases belonged to the severe category in W2 compared to 37.5% in W1. W2 patients demonstrated higher transaminase levels [SGOT, 108.3 (99.3) v/s 54.6 (69.3);SGPT, 97.6 (82.3) v/s 58.7 (69.7)] with respect to W1. Similarly, the CT severity score for W2 [29.5 (6.7)] was higher than W1 [23·2 (11·5)][All P<0.05]. The proportion of patients requiring oxygen (81.8% v/s 11.2%), high flow nasal cannula (11.4% v/s 5.6%), non-invasive ventilation (41.2% v/s 1.5%), invasive ventilation (24.5% v/s 0.9%), as well as ICU/HDU admissions (56.4% v/s 12.0%) was higher for W2 as compared with W1. The measured case fatality rate varies from 29% for W2 to 9.6% for W1. Interpretation: Higher age, oxygen requirement, ventilator requirement, ICU admission, and organ impairment are more prevalent in the admitted COVID-19 cases during the second wave that has hit India compared to the first wave and associated with more fatalities. Strategy for another wave should be planned accordingly.Funding Information: None.Declaration of Interests: We declare that we have no conflicts of interest.Ethics Approval Statement: Ethical approval was obtained (CTRI/2020/08/027169).