Introduction: Antibody-mediated rejection (ABMR) is a severe form of rejection, mediated by complement (C). C1 inhibitor (C1INH, Berinert®) inhibits classic and (MBL/MBLSP) pathways of C activation. Here we undertook a placebo-controlled, single center study using C1INH in highly sensitized (HS) patients for prevention of ABMR. Patients & Methods: From 12/2011 to 4/2012, 20 consecutive HS patients {CPRA >50%, DSA(+) and FCMX(+)} desensitized with IVIG + rituximab were enrolled and randomized 1:1 to receive C1INH (20u/kg/dose) vs. Placebo (NS) administered intra-operatively, then 2X weekly for 7 additional doses. Post-transplant, evidence of DVT (Wells Criteria), other AEs/SAEs and C3, C4, C1INH levels were monitored. All patients received Campath-1H induction and were maintained on Prograf/Cellcept/Pred. Results: Two patients (20%) in C1INH vs. 3 patients (30%) in NS developed SAEs. C1INH levels {C1 function (p = 0.0007) & C1INH antigen % (p = 0.013)} increased with C1INH treatment. C3 levels on day 30 increased in the C1INH group (p= 0.005). C4 levels were significantly higher in the C1INH group at all time points.Figure: No Caption available.No patient in the C1INH group developed ABMR during the study period. Two patients (20%) developed ABMR outside of study period. 30% of NS treated developed ABMR, one during study period.Table: No Caption available.Conclusions: Important observations from this initial trial in human transplantation of C1INH include: C1INH appears safe in the post-transplant period. Second, C1INH administration resulted in significant elevations of C1INH, C3 and C4 levels, suggesting inhibition of systemic C activation by C1INH. Finally, no ABMR episodes were observed during the treatment period with C1INH. IND #14363, NCT01134510. DISCLOSURE:Jordan, S.: Grant/Research Support, CSL-Behring.