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The Major Histocompatibility Complex (MHC) harbors key genes of the immune response that are likely useful as biomarkers for infectious diseases. However, little is known about their microRNAs and what role they play in infections. The present study aimed to describe the miRNA genes in the MHC (MHC-miRNA), their variability and associations with infectious diseases. Additionally, MHC-miRNA host and target genes were also evaluated in associations with infectious diseases. Surveys in several databases and literature reviews identified 48 MHC-miRNA genes, with high SNP and CNV variability able to disrupt MHC-miRNA expression and putatively under selective pressure. Eight MHC-miRNAs were found inside or close regions of classical MHC rearrangements (RCCX and DRB genome organization). The proportion of MHC-miRNAs associated with infections (23%) was higher than the proportion found for the 1917 hsa-miRNA (4%). Additionally, 35 MHC-miRNAs (57%) have at least one of their target genes associated with infectious diseases, while all nine MHC-miRNA whose host genes were associated with infections have also their target genes associated with infections, being host and target genes of five MHC-miRNAs reported to be associated with the same diseases. This finding may reflect a concerted miRNA-mediated immune response mechanism triggered by infection., (Copyright © 2019. Published by Elsevier Inc.)