Human Leukocyte Antigen Antibodies (HLA-Ab) generated by transplant patients are the primary cause of chronic allograft rejection. B-cell activating factor in serum (sBAFF) is a B-cell differentiation and maturation cytokine that might be a biomarker for HLA-Ab production. A new sBAFF detection assay was developed and used to test a total of 139 serum samples from 17 non-sensitized male, 18 transfusion, and 21 kidney transplant patients. sBAFF was correlated with HLA-Ab production; non-sensitized males with low HLA-Ab had an average sBAFF level of 48,441 pg/mL versus 183,975 pg/mL for highly-sensitized transfusion patients (p<0.0001). Temporal analysis between sBAFF and HLA-Ab supports a lag effect where a rise in sBAFF precedes a rise in average HLA-Ab by 10 days and a rise in donor-specific HLA antibody by 19 days. Our findings suggest that sBAFF levels may be predictive of imminent HLA-Ab production and may facilitate earlier and more effective treatment of HLA-Ab.