Mannose-binding lectin (MBL) glycoproteins in blood can selectively recognise lectins on the surface of bacteria, and play an important role in natural immunity. Micro RNAs (miRNAs) are key molecules that regulate gene expression at the post-transcriptional level in vivo, and their pathways are specific and effective. Previous studies indicate that small RNAs such as miRNAs perform regulatory roles in immunology. Herein, we investigated differential expression of miRNAs during MBL protein immunotherapy in sheep following treatment with different MBL genotypes (resistant and susceptible), and identified miRNAs linked to different target genes and pathways. RNA was extracted from liver tissue of resistant and susceptible sheep, miRNAs were identified by high-throughput sequencing, and differentially expressed miRNAs were analysed by SOAP to predict target genes and biological pathways. Results: Some miRNAs (oar-mir-143, oar-mir-10b, oar-mir-382, oar-mir-432 and oar-mir-379) were up-regulated, while others were down-regulated. GPATCH3 and DNAJC5 were predicted target genes of oar-mir-379, DMRT1 and GATA4 were linked to oar-mir-382, and oar-mir-432 was associated with STAT2, DMRT1 and ATG16L1. Identification of miRNAs differentially expressed in resistant and susceptible sheep may expand our understanding of miRNAs in immune regulation, and the role of MBL in innate immunity.