Predicting long-term outcomes in renal transplant recipients is essential to optimize medical therapy and determine the frequency of post-transplant pathologic and serologic monitoring. Non-adherence and HLA mismatch are risk factors that have been associated with poor long-term outcomes and may help individualize care. In the present study class II HLA mismatches were determined at the HLA epitope level in 195 renal transplant recipients in whom medication adherence was prospectively measured using electronic monitors in medication vial caps. Recipients were grouped by medication adherence and high (≥10 HLA-DR, ≥17 HLA-DQ) or low epitope-mismatch load. We found that the combination of higher epitope mismatch and poor adherence acted synergistically to determine the risk of rejection or graft loss.Non-adherent recipients with HLA-DR epitope mismatch ≥10 had increased graft loss (35% vs. 8%, p<0.01) compared to adherent recipients with low epitope mismatch. At the HLA-DQ locus non-adherent recipients with HLA-DQ epitope mismatch ≥17 had increased graft loss (33% vs. 10%, p<0.01) compared to adherent recipients with low epitope mismatch. Subclinical non-adherence early post-transplant combined with HLA class II epitope mismatch may help identify recipients that could benefit from increased clinical, pathologic, and serologic monitoring.

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