The clinical significance of pre-txp donor specific anti-HLA-DQ antibodies (Ab) detected by luminex single antigen bead assays in the absence of reactivity with B cells is unclear. This discrepancy in Ab reactivity could be due variation in DQA1/DQB1 alleles, structural variations caused by the presented peptide, or reactivity to “cryptic epitopes”. Furthermore, other cell-specific factors may influence the reactivity of these Abs. Here we report a case of an accelerated rejection in a kidney txp and a case of chronic lung allograft dysfunction (CLAD), both were associated with the presence of pre-txp anti-DQ DSA. These anti-DQ antibodies were not reactive with B cells using a sensitive FCXM. Case 1 is a 50-y/o Caucasian female, received her first kidney txp from an HLA compatible living donor. Her serum Creatinine (Cr) was 1.07 on post-operative day 6 (POD). On POD 8, Cr increased to 3.08, with a 4-fold increase in DSA; kidney biopsy was consistent with AMR (Table 1); notably, Abs remained non-reactive with B cells. After treatment with several cycles of plamapheresis, IVIG, and augmented IS, patient’s DSA decreased significantly and her Cr decreased to 1.61. Eight months post-txp, patient’s kidney function is stable with a Cr at 1.39 and the DSA decreased to pre-txp level (Table 1). Case 2 is 62 y/o Caucasian male who received a left single lung txp for interstitial lung disease from an HLA compatible donor. The early post-operative course was uncomplicated. Pulmonary function test declined 3 months post-txp. The patient had a 3-fold increase in the pre-txp anti-DQ6 (allele-specific) DSA; lung biopsies showed features of AMR (Table 1); notably, Abs remained non-reactive with B cells. Despite aggressive treatment with IV solumedrol, IVIG and rituximab, patient developed a progressive CLAD and received a second transplant from a DQ6 negative donor. Further investigations are needed to confirm these observations and determine the clinical significance of anti-DQ antibodies that are not reactive with B cells.