Aim To analyze the impact of donor-specific HLA-C antibodies (DSA) on crossmatch (XM) and transplant (tx) outcome. Methods HLA antibodies (Ab) were analyzed using One Lambda (OL) single antigen beads (SAB). 334 T-cell flow XMs targeting a single HLA-A, B or C allotype were performed. Relationships between the strengths of XM (MCS) and DSA (MFI) were assessed by Pearson’s correlations. Outcomes of 3 organ txs performed with strong (MFI > )10 K) pre-formed HLA-C DSAs were assessed. Results Strong and linear positive-correlations were observed between MCS and MFI of single HLA-A (R2 = 0.88) or HLA-B (R2 = 0.71) targeted XMs [Fig. A]. Conversely, a poor correlation (R2 = 0.19) was obtained with HLA-C targeted XMs. To avoid multi-epitope targeting, we focused our analyses on 66 T cell XMs that were performed using sera with strong Abs (MFI > 10 K) targeting only a single C1 (Cw1,7,8,9,10,12,14,16, B46 and B73) or C2 (Cw2,4,5,6,15,17 and 18), the dimorphic epitopes of HLA-C that bind different isoforms of KIR2D receptors [Fig. B & C]. Two sera with anti-C1 reactivity showed distinct T cell-binding patterns – 1 caused +ve XMs and another caused −ve XMs [Fig.D] when targets express C1-containing HLA-C allotypes. Another 2 sera with anti-C2 reactivity showed distinct bindings – 1 caused +ve XMs and another caused −ve XMs when targets express C2-containing HLA-C allotypes. One of the patients displaying anti-C2 reactivity received a kidney tx with pre-formed Cw6 DSA (MFI = 20 K) but −ve XM, and no rejection was observed in 1 year post-tx. Some patients display strong (MFI > 10 K) reactivity to subsets of Cw-beads: Cw1,12,15 (Fig. E) or Cw2,4,5,6,8,9,10,14,16,17,18 (Fig. F). These Abs neither cause +ve XM nor harm the allograft, and are self-decayed post-tx. Conclusions Not all HLA-C Abs detected by OL SAB assay bind to cells. Despite high MFI, the no-binding HLA-C DSAs do not harm the allograft. The clinical impact of HLA-C Abs must be judged by their cell binding.