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Objectives: Donor-specific antibodies (DSAs) are associated with increased cardiac graft loss. We applied a C1q solid-phase assay in parallel with the standard immunoglobulin G (IgG) single antigen bead (SAB) assay to examine the correlation of circulating complement-fixing donor-specific antibodies and the presence of C4d in endomyocardial biopsy (EMB) specimens.Methods: We retrospectively studied the relationship of C1q+ DSAs and C4d immunofluorescence (IF) in 49 EMB specimens from 44 heart transplant recipients who had concurrent EMB, C4d IF, and DSA measurements. We applied a C1q SAB in parallel with the standard IgG SAB assay to examine the DSA profiles in heart transplant patients posttransplant.Results: A better concordance is observed between C1q+ DSAs with C4d IF+ compared with IgG DSAs with C4d IF + (40% vs 24%, P = .02). However, the correlation of C1q DSAs with C4d IF is not statistically significant (P = .24). Importantly, C1q+ DSAs were observed in 16 of 17 cases with C4d IF+; 24 cases had circulating C1q+ DSAs without detectable C4d staining, suggesting that that the presence of C1q+ DSAs may precede the detection of C4d deposition in EMB specimens and/or the development of antibody-mediated rejection.Conclusions: In this cohort of 44 patients, no significant correlation was observed between circulating C1q DSAs and C4d IF in EMB specimens. Additional studies are needed to further evaluate the association of C1q DSAs with EMB specimens and C4d staining.