Background There are preliminary studies about the association between COVID-19 and ABO phenotypes and the results are controversial. There are only two studies which investigated the association of Rh blood groups in addition to ABO with COVID-19; however, in the statistical analysis ABO and Rh blood groups have been considered separately. Therefore, the present case-control study was performed to determine the association of COVID-19 with ABO blood groups considering the Rh blood groups simultaneously. The study was conducted in Kunduz COVID-19 treatment specific center, Spin-Zar Hospital (Kunduz Province, North East Afghanistan). A total of 301 confirmed COVID-19 cases and 1039 healthy blood donors as control group were included in the study. Results The Rh− phenotype strongly increased the risk of COVID-19 (OR = 2.97, 95% CI 1.86–3.89, P < 0.001). Although blood group A increased the risk of developing COVID-19, the association did not reach statistical significance. In analysis of the combination phenotypes, the A− blood group remarkably increased the risk of COVID-19 (OR = 7.24, 95% CI 3.62–14.4, P < 0.001). Multivariate analysis revealed that the interaction of Rh and ABO is significant (P < 0.013). Conclusion These findings indicate that susceptibility to COVID-19 is strongly associated with A− blood group.