Abstract The origin and physiopathological relevance of catalytic antibodies is not well understood owing to the fact that catalytic antibodies have been studied in relatively small cohorts of patients with rare diseases and/or without systematic follow-up. In the present study, we have followed the evolution of the levels of catalytic IgG in a large cohort of 100 renal transplant patients over a 2-year period. Prior to transplant, hydrolysis of the generic substrate PFR-MCA was greater for patients’ IgG than for a therapeutic preparation of pooled IgG from healthy donors (6.6±0.9 vs 0.65±0.03 fmol/min per pmol). Renal transplant was marked by a drastic decrease in levels of catalytic IgG over 3 months (6.6±0.9 vs 2.4±0.2 fmol/min/pmol; P<0.0001) followed by a steady increase at 12 months (3.2±0.3 fmol/min/pmol; P=0.015) and further at 24 months (5.1±0.6 fmol/min/pmol; P=0.004). When divided into quartiles based on the rates of IgG-mediated PFR-MCA hydrolysis measured in pre-transplant samples, the IgG catalytic activity in the upper quartile of patients was significantly high both pre-transplant (12.03±1.6 vs 2.7±0.2 fmol/min/pmol, P<0.0001) and 24 months post-transplant (6.8±1.2 vs 4.6±0.7, fmol/min/pmol, P=0.0004). Interestingly, IgG-mediated hydrolysis of a model protein substrate, pro-coagulant factor VIII, did not correlate with that of PFR-MCA prior transplantation, while it did 12 months post-transplant (P<0.0001, R2=0.4). Taken together, our results suggest that the level of circulating catalytic IgG under pathological conditions is an intrinsic property of each individual’s immune system, and that recovery of pre-transplant levels of catalytic IgG is accompanied by changes in the repertoire of target antigens.