Background: The COVID-19 pandemic has resurfaced in India as a hardhitting 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 pandemic (SARS-CoV-2) in a single tertiary care center in India. Methods: In this retrospective observational study, we examined the demographic profile, symptoms at presentation, 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. Results: The age group affected most in the W2 is 50.5 (17.7) versus 37·1 (16·9) years for W1. The baseline oxygen saturation is lower in W2, being 84·0 (13·4) % compared with 91·9 (7·4) % in W1 [SpO2 Conclusion: Higher age, oxygen requirement, ventilator requirement, ICU admission, and organ failure are more prevalent in the admitted COVID-19 cases during the second wave that hit India than in the first wave and are associated with more fatalities. Strategy for another wave should be planned accordingly.