This study evaluates the ability of donor-derived cell-free DNA (dd-cfDNA) to detect kidney transplant rejection before biopsy-proven rejection. The ProActive registry study, a multicenter observational study, analyzed 424 patients with ≥1 dd-cfDNA test within 6 months before biopsy. The results showed that dd-cfDNA levels were significantly elevated 5 months before antibody-mediated rejection (ABMR) biopsies and 2 months before T cell-mediated rejection (TCMR) biopsies, compared with nonrejection biopsies. Serum creatinine levels did not show significant elevation before rejection. Among patients with nonrejection biopsies, those with ≥2 increased dd-cfDNA results had significantly lower estimated glomerular filtration rate (eGFR) compared with those with 0 or 1 increased dd-cfDNA result. These findings suggest that dd-cfDNA is an early indicator of biopsy-proven rejection, particularly ABMR, and may help identify patients at high risk of ongoing or future rejection, requiring closer monitoring, biopsy, or other management changes. The study highlights the potential of dd-cfDNA as a noninvasive biomarker for early detection of rejection, improving outcomes in kidney transplant recipients.This study evaluates the ability of donor-derived cell-free DNA (dd-cfDNA) to detect kidney transplant rejection before biopsy-proven rejection. The ProActive registry study, a multicenter observational study, analyzed 424 patients with ≥1 dd-cfDNA test within 6 months before biopsy. The results showed that dd-cfDNA levels were significantly elevated 5 months before antibody-mediated rejection (ABMR) biopsies and 2 months before T cell-mediated rejection (TCMR) biopsies, compared with nonrejection biopsies. Serum creatinine levels did not show significant elevation before rejection. Among patients with nonrejection biopsies, those with ≥2 increased dd-cfDNA results had significantly lower estimated glomerular filtration rate (eGFR) compared with those with 0 or 1 increased dd-cfDNA result. These findings suggest that dd-cfDNA is an early indicator of biopsy-proven rejection, particularly ABMR, and may help identify patients at high risk of ongoing or future rejection, requiring closer monitoring, biopsy, or other management changes. The study highlights the potential of dd-cfDNA as a noninvasive biomarker for early detection of rejection, improving outcomes in kidney transplant recipients.