Background/Aim: Renin-angiotensin system (RAS) is present in a diverse type of cells and plays an important role in lung physiology and pathophysiology. Angiotensin converting enzymes (ACE) are part of the RAS system. There are still controversies about the association of I/D polymorphisms of ACE1 with COVID-19 severity. The goal of the study was to determine whether there is an association of the I/D polymorphism with severity of in Mexican patients. Patients and Methods: The study included voluntary participants: 53 healthy individuals negative to RT-PCR COVID-19 (control), and 165 patients positive to COVID-19. Severity was defined by the need of hospitalization, invasive ventilation, shock, or multiple organ failure. The patient group consisted of 28 asymptomatic, 82 with mild, and 55 with severe COVID-19. I/D polymorphism was determined by PCR. Rutinary laboratory tests were performed in all the participants. Results: DD polymorphism was significantly associated with severe COVID-19, independently of comorbidities, or any other variable. Receiver operator characteristic curves demonstrated association of low total cholesterol, low high-density lipoproteins, and high c-reactive protein with severity of COVID-19. Conclusion: The DD polymorphism was associated with the course of the infection and severity of COVID-19 in a sample of Mexican patients.The renin-angiotensin system (RAS) is present regulates diverse cellular processes. Angiotensin converting enzymes (ACE), are part of RAS. ACE1 has two main functions: production of angiotensin II and degradation of bradykinin, whereas the main functions of ACE2 are degradation of angiotensin II and production of ang1-7. ACE1 and ACE2 have opposite functions (1). The ACE1 gene maps on chromosome 17, locus 17q23 (1). The main polymorphisms of ACE1 are insertion (I) or deletion (D) of a 287-base pair segment, which produces three polymorphisms, DD, ID, and II (2). ACE activity and ACE levels in plasma depend on the D polymorphism (1). DD is related to higher concentrations of angiotensin II in plasma and has been associated with hypertension, cerebrovascular disease, myocardial infarction, and increased mortality in people younger than 65 years (1, 3). The D allele is associated with diabetic nephropathy and left ventricular hypertension, whereas the I allele is associated with high performance exercise (1). The ID polymorphism has been associated with lung acute and chronic diseases such as chronic obstructive pulmonary disease (COPD), pulmonary hypertension, asthma, lung cancer, and pulmonary sarcoidosis (3).It is known that ACE2 is the receptor of SARS-COVID-19 (4). Therefore, regulation of ACE1 and ACE2 has been extensively explored in COVID-19. The association of DD polymorphism with severity of COVID-19 seems to depend on ethnicity, sampling bias, biological factors, study design, data analysis, and time of sampling (wave of COVID-19) (2). 433