Abstract Background and Aims Kidney transplant recipients (KTRs) are particularly susceptible to infections due to their continuous immunosuppressive treatment, the presence of other comorbidities, and, in some cases, impaired kidney function. While previous research has identified certain risk factors for severe COVID-19 in KTRs, comprehensive data at a national level—minimizing regional or center-specific influences—remains scarce. Our study aimed to fill this gap by examining risk factors for severe COVID-19 at a national level. Thus, we conducted a retrospective analysis of COVID-19 outcomes, alongside demographic, clinical, and medication-related risk factors associated with hospitalization and mortality due to COVID-19, within a comprehensive national cohort of Swedish KTRs over the initial two years of the pandemic. Method We assessed the outcomes and identified risk factors associated with hospitalization and mortality from COVID-19 among all kidney transplant recipients in Sweden who were alive as of January 1, 2020 during the first two years of the pandemic (2020-2021). We utilized data from the Swedish Renal Registry (SRR) and other interconnected healthcare registries. The SRR is a nationwide registry, with almost complete coverage (>97%) of patients with kidney replacement therapy in Sweden, including KTRs. Through multivariable adjusted logistic regression models, we systematically analyzed this data to pinpoint risk factors contributing to severe COVID-19 cases in this specific patient population. Results There were 5,824 KTRs in Sweden on January 1, 2020 with a mean age 58 years, 64% men. An increased risk of severe COVID-19 was observed for patients aged between 49 to 68 years, with the highest point estimate for patients aged 49-58 years (OR 2.26, 95% CI 1.50-3.45) and those who underwent a prolonged duration of dialysis before their transplantation (aOR 1.04, CI 95% 1.01-1.07 [per one year increase]). Conversely, KTRs with a longer elapsed time since the transplantation and those who had received a kidney from a living donor had a lower risk of severe COVID-19. Compared to KTRs who were transplanted less than a year ago, those who had received their transplant 6-10 years ago or >10 years ago had an about 50% lower risk of being hospitalized or die from COVID-19 (aOR 0.49, CI 95% 0.35-0.68 and aOR 0.55, CI 95% 0.40-0.74, respectively). While no significant correlation was observed directly between hypertension and severe COVID-19, a significant association was identified with the increasing number of antihypertensive medications prescribed to a patient (P-value <.0001). Furthermore, treatment with mycophenolate mofetil and the use of a higher number of immunosuppressive drugs were associated with a higher risk of severe COVID-19. The use of proton pump inhibitors was also linked to an increased risk of severe COVID-19 (aOR 1.66, 95% CI 1.33-2.07). Conclusion Our study reveals several critical insights into the risk factors associated with severe COVID-19 among KTRs in Sweden. A key finding is the increased risk observed in individuals of working age, potentially due to higher exposure to the virus. Additionally, our findings suggest that the severity of comorbidities, rather than the presence of comorbidities themselves, may play a more significant role in increasing the risk of severe COVID-19. Importantly, our research sheds light on the potential impact of proton pump inhibitor (PPI) therapy, as a modifiable risk factor in the management of COVID-19. In general, our findings are instrumental in developing more targeted prevention and treatment strategies for COVID-19 in KTRs, aiming to improve care for this particularly vulnerable group.