Immunoglobulin G (IgG) subclasses IgG1 (G1) and lgG3 (G3) can induce complement dependent cytotoxicity (CDC) and bind to Fc receptors (FcR), which induces phagocytosis and antibody dependent cellular cytotoxicity. In contrast, IgG2 has low CDC activity, lgG4 (G4) has no CDC activity, and neither binds high affinity FcR. Seven transplant recipients were analyzed for G1-G4 human leukocyte antigen (HLA) donor-specific antibodies (DSAs); six had active rejection and one had stable function. Patients with rejection had equal numbers of DSAs, which were G1 and G3, but no G4. The predominant DSAs were directed against HLA Class II proteins. Even with successful anti-rejection therapy, DSA persisted, albeit in several instances with lowered levels. Our findings are consistent with the presence of CDC-inducing G1 and G3 subclass DSAs during rejection. One heart transplant recipient followed for over 42 months had consistent, continuous G4 HLA DSA and stable function. We hypothesize that the presence of G4 DSA in the heart transplant recipient is akin to the allergen specific G4 that has been found in allergic desensitization tolerance, controlled by regulatory T-cells, and that manipulating G4 class switching through HLA antigen desensitzation could produce a tolerant state.