Background: COVID-19 pandemic, which started in late 2019, has brought various ups and downs worldwide. Planned policies were highly useful in the first wave of the COVID-19 pandemic in Iran. However, due to several reasons, the country faced the second wave. Objectives: The current study aimed to compare patients’ features in the first two waves of the COVID-19 pandemic in the city of Tehran, Iran. Methods: Following a retrospective, cross-sectional design, the current study was carried out on 5000 suspected/confirmed COVID-19 cases who were randomly selected from all cases transferred by ambulance to hospitals located in the city of Tehran. The first wave of the COVID-19 epidemic was from February 20 to May 04, 2020, and the second wave was from May 05 to August 05, 2020. Data for both waves, were collected using a researcher-made checklist. Results: In this study, data of 5000 suspected/confirmed COVID-19 cases were analyzed (2773 cases belonged to the first wave and 2227 to the second one). The mean age of patients (P < 0.001), the frequency of cigarette smoking (P < 0.001), opium abuse (P = 0.004), and the presence of underlying diseases (P < 0.05) were more frequent in the second wave than in the first one. The notable finding in this study was the significant increase of non-respiratory symptoms of patients in the second wave. The number of cases who reported close contact with COVID-19 patients was higher in the second wave. Also, hypoxia, intubation during the hospital stay, length of hospitalization, and mortality rates were significantly lower in the second wave. During the second wave, the odd ratio of positive findings in lung CT-scan was 3.4 (95% confidence interval: 2.51 to 4.55) compared to the first wave (P < 0.001). Conclusions: This study demonstrated considerable differences between the first and second waves of the COVID-19 pandemic concerning the patients’ features.