Exposure to different tissues such as in organ transplantation, pregnancy, or blood transfusions, can result in the production of antibodies against human leukocyte antigens (HLA). It has been demonstrated that the presence of anti-HLA donor-specific antibodies (DSA) among renal transplant recipients is a substantial risk factor for graft deterioration. The novel coronavirus disease 2019 (COVID-19) brought on by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been hypothesized to cause an unusual immunological dysregulation that can in some populations, such as kidney transplant recipients, lead to a number of complications. The outcomes of 321 kidney transplant recipients who had COVID-19 illness were assessed in this prospective observational cohort study. Additionally, after an acute COVID-19 infection, factors influencing the development of HLA de novo DSA and non-DSA specificities were assessed. Logistic regression analysis was used to analyze the independent factors associated with the development of anti-HLA de novo DSA and non-DSA. A stepwise multivariable logistic regression was used to assess the association between potential risk factors and the development of anti-HLA de novo DSA and non-DSA specificities after COVID-19, adjusting for known confounders. The variables evaluated were acute COVID-19 characteristics (i.e., presentation, need for hospitalization), demographic characteristics (i.e., age, gender, and primary renal disease), clinical characteristics (i.e., various comorbidities), and post-COVID-19 sequelae. Anti-HLA de novo DSA developed in 18,7% of patients, and they were more likely to be female. Anti-HLA class I antibodies developed de novo in 84 (26,3%) patients, while anti-HLA class II antibodies developed de novo in 83 (25,9%) patients. There was an increased prevalence of certain anti-HLA class II antibodies. The development of DSA, HLA-DQ, and HLA-DR was predicted by the history of graft rejection. Obesity appears to serve a protective role against the emergence of de novo DSA. De novo DSA and HLA-DR formation was positively linked with intravenous immunoglobulin use, CMV-hyperimmune globulin use, and decreased doses of immunosuppression during acute infection. Better allograft function during acute disease was a protective factor against the formation of HLA-DQ and HLA-DR. Positive predictors of de novo DSA development were graft biopsy and reactivation of EBV after infection. In conclusion, these findings suggest that the SARS-CoV-2 virus has an immunomodulatory effect and may be associated with an increase in mortality in this population. Further research with long-term follow-up is required.