This paper includes a review of the relative importance of pretransplant complement-fixing and non-complementing-fixing human leukocyte antigen (HLA) and non-HLA antibodies (Abs). Sera from 565 adult cardiac transplant recipients were retrospectively analysed for the presence of HLA antibodies using complement-dependent cytotoxicity (CDC), HLA-coated Luminex beads, and C4d deposition on Luminex beads and results were correlated with graft survival. Of 565 patients, 14 had CDC-positive donor-specific Abs (DSA) before their transplant. This number was increased by 53 using Luminex beads; of these, 19 had DSA by Luminex. Patients negative for CDC crossmatch, but Luminex positive with DSA demonstrated poor 1-year survival (42%) compared with 77% 1-year survival of patients with CDC-negative, Luminex positive non-donor-specific Abs. The effect of donor-specific Abs on allograft survival was further analyzed according to titer, immunoglobulin subclass, and ability to fix C4d onto Luminex beads. The ability to fix C4d, but not Ab titer or Ig subclass, was strongly associated with poor allograft survival (p = 0.0002). A retrospective analysis of sera from 616 cardiac transplant patients indicated the presence of immunoglobulin M complement-fixing non-HLA Abs was associated with early graft failure and a diagnosis of primary graft failure. In conclusion, complement-fixing Abs to relevant antigens are associated with poor allograft survival after heart transplantation.