HLA-incompatibility is a major factor associated with outcome of allogeneic stem cell transplantation, but little is known on the impact of isolated HLA-C mismatches. We analyzed the outcome of 114 CML patients transplanted with marrow from unrelated donors of whom 24 were mismatched for HLA-C only (9/10 match). Univariate estimates of 5-year survival (SRV) (median follow-up: 47 months) in the HLA-matched group were 68+/-12 vs 42+/-20% (P=0.03) for the patients mismatched for HLA-C only and 33+/-33% in the mismatched group (non-HLA-C single mismatches and multiple mismatches) (P=0.0004). Disease stage, GVHD-prophylaxis (T-cell depletion), CMV-status and HLA-incompatibility were the risk factors associated (all P< or =0.005) with poor outcome. In the multivariate analysis, patients mismatched for loci other than HLA-C were at high risk of an adverse outcome (death: RR, 2.9; CI, 1.6-5.4, P=0.008, transplant-related mortality (TRM): RR, 3; CI, 1.5-5.9, P=0.0015). For patients mismatched for HLA-C only, the increased risk was of borderline significance (death: RR, 1.9; CI, 1-3.9, P=0.06, TRM: RR, 2.1; CI, 1-4.5, P=0.07). In spite of their lower expression, HLA-C antigens still represent relevant transplantation barriers that should be considered when searching for an unrelated donor.