Histologicanalysis of the allograftbiopsy specimen is the standardmethodused todifferentiate rejection fromother injury in kidney transplants.Donor-derived cell-freeDNA(dd-cfDNA) is a noninvasive test of allograft injury thatmay enablemore frequent, quantitative, and safer assessment of allograft rejection and injury status. To investigate this possibility, we prospectively collected blood specimens at scheduled intervals and at the time of clinically indicated biopsies. In 102 kidney recipients, we measured plasma levels of dd-cfDNA and correlated the levels with allograft rejection status ascertained by histology in 107 biopsy specimens. The dd-cfDNA level discriminated between biopsy specimens showing any rejection (T cell-mediated rejection or antibody-mediated rejection [ABMR]) and controls (no rejection histologically), P,0.001 (receiver operating characteristic area under the curve [AUC], 0.74; 95%confidence interval [95%CI], 0.61 to 0.86). Positive and negativepredictive values for active rejection at a cutoff of 1.0% dd-cfDNA were 61%and84%, respectively. TheAUCfor discriminatingABMRfromsampleswithoutABMR was 0.87 (95%CI, 0.75 to 0.97). Positive and negative predictive values forABMRat a cutoff of 1.0% dd-cfDNA were 44% and 96%, respectively. Median dd-cfDNA was 2.9% (ABMR), 1.2% (T cell-mediated types $IB), 0.2% (T cell- mediated type IA), and 0.3% in controls (P=0.05 for T cell-mediated rejection types$IB versus controls). Thus, ddcfDNA may be used to assess allograft rejection and injury; dd-cfDNA levels ,1% reflect the absence of active rejection (T cell-mediated type $IB or ABMR) and levels .1% indicate a probability of active rejection.