Donor‐specific alloantibodies (DSA), especially those fixing complement, may pose a particular immunologic risk to transplant recipients. To assess the clinical impact of C4d‐ or non‐C4d‐fixing (IgG) HLA sensitization, pretransplant sera obtained from 338 kidney allograft recipients prescreened by FlowPRA were retrospectively evaluated by Luminex single antigen (SA) testing using a novel fluorescent‐labeled anti‐C4d reagent for detection of antibody‐triggered C4d deposition in addition to IgG binding. Recipients with [IgG]DSA (n = 39) showed a substantially higher rate of C4d positive rejection (33%) than 16 patients with [IgG] non‐DSA (0%) or 283 antibody‐negative patients (4%, multivariate analysis excluding retransplantation because of high co‐linearity: P < 0.0001), and adversely affected 5‐year death‐censored graft survival  (74% vs. 81% and 90%, respectively, multivariate model: P < 0.05). [C4d] DSA (n = 21) and [C4d] non‐DSA (n = 25) increased rates of C4d positive rejections to a similar extent (24% and 28% vs. 4% in recipients without C4d‐fixing reactivity; multivariate analysis: P ≤ 0.002) with a trend towards adverse 5‐year graft survival (76% and 76% vs. 90%; P ≤ 0.2). In conclusion, Luminex‐based characterization of HLA sensitization may be a useful strategy for risk stratification. Possibly as a result of intensified immunosuppression in presensitized recipients, identification of C4d‐fixing DSA was not associated with a further increase of rejection and graft loss rates.