Objective: To evaluate patient demographic characteristics and risk factors for mortality during the first and the second wave among COVID-19 patients in a tertiary care hospital of India. Methods: Data were taken from the hospital\'s electronic system for COVID-19 patients from August 2020 to December 2020, and the second from January 2021 to May 2021. The mortality rate, demographic and clinical characteristics, laboratory profile, and reasons for the death of the two waves were retrieved and compared, and the risk factors of the two waves were determined. Results: In the first wave, 1177 COVID-19 cases visited the hospital and 96 (8.2％) died. In comparison, the death rate in the second wave was significantly higher (244/2038, 12.0％) (P<0.001). No significant difference in age [60 (50-69) vs. 60.5 (53-70), P=0.11] or gender (P=0.34) was observed between the two waves. Compared to the first wave. there were significantly more cases with fever, cough, weakness, loss of taste and smell, and sore throat during the second wave (P<0.05), but significantly fewer cases with kidney disease (6.6％ vs. 13.5％, P=0.038) and diabetes mellitus (35.7％ vs. 50.0％, P=0.015). Besides, during the second wave, more patients had abnormal X-ray findings, higher levels of lymphocytes and serum ferritin (P<0.05). In addition, there were significant differences in the rate of death cases with acidosis, septic shock, acute kidney injury, diabetes mellitus, cardiovascular events, hypothyroidism (P<0.05). Multivariate regression showed that during the first wave, age (OR: 1.10; 95％ CI: 1.02-1.21), diabetes mellitus (OR: 3.16; 95％ CI: 2.08-3.53), and abnormal X-ray (2.67; 95％ CI: 2.32-2.87) were significant independent risk factors of mortality; while in the second wave, age (OR: 1.13; 95％ CI: 1.12-1.28), diabetes mellitus (OR: 8.98; 95％ CI: 1.79-45.67), abnormal X-ray (OR: 12.83; 95％ CI: 2.32-54.76), high D-dimer (OR: 10.89; 95％ CI: 1.56-134.53), and high IL-6 (OR: 7.89; 95％ CI: 1.18-47.82) were significant independent risk factors of mortality . Conclusion: Overall mortality and incidence of severe diseases are higher in the second wave than the first wave. Demographic characteristics, co-morbidities, and laboratory inflammatory parameters, especially D-dimer and IL-6, are significant risk facors of mortality during the COVID-19 pandemic.