No allogeneic CTL responses are detected in vitro for the isolated mismatch in the HLA alleles C*03:03 and C*03:04. Hematopoietic stem cell transplantation (HSCT) with unrelated donors (UD) showed no association between the HLA-C allele mismatches (CAMM) with adverse outcomes; whereas antigen mismatches at this and other HLA loci have deleterious effects. It was hypothesized that the absence of effect of the CAMM resulted from the predominance of the mismatch C*03:03/C*03:04. Cohorts of 4,779 and 1,854 patients with hematologic malignancies receiving UD HSCT matched in 8/8 and 7/8 HLA alleles were examined. Transplants mismatched in HLA-C antigens or mismatched in HLA-A, B, or DRB1 presented significant differences (p<0.0001) in mortality (HR=1.37, 1.30), disease free survival (HR=1.33, 1.27), treatment related mortality (HR=1.54, 1.54), and grade III-IV acute graft-versus-host disease (HR=1.49, 1.77) compared to the 8/8 group; transplants mismatched in other CAMM had similar outcomes with HR ranging 1.34-172 for these endpoints. In contrast, the C*03:03/C*03:04 mismatched and the 8/8 matched groups had virtually identical outcomes with HR ranging 0.96-1.05. The previous finding that CAMM do not associate with adverse outcomes is explained by the predominance (69%) of the permissible mismatch C*03:03/03:04 in this group; this mismatch is better tolerated than other HLA mismatches.