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<i>Maedi-visna</i> virus (MVV) and caprine arthritis encephalitis virus (CAEV), referred to as small ruminant lentiviruses (SRLVs), belong to the genus <i>Lentivirus</i> of the Retroviridae family. SRLVs infect both sheep and goats, causing significant economic losses and animal welfare damage. Recent findings suggest an association between serological status and allelic variants of different genes such as <i>TMEM154</i>, <i>TLR9</i>, <i>MYD88</i> and <i>CCR5</i>. The aim of this work was to investigate the role of specific polymorphisms of these genes in SRLVs infection in some sheep flocks in Italy. In addition to those already known, novel variants in the <i>TMEM154</i> (P7H, I74V, I105V) gene were detected in this study. The risk of infection was determined finding an association between the serological status and polymorphisms P7H, E35K, N70I, I74V, I105V of <i>TMEM154</i>, R447Q, A462S and G520R in <i>TLR9</i> gene, H176H* and K190K* in <i>MYD88</i> genes, while no statistical association was observed for the 4-bp deletion of the <i>CCR5</i> gene. Since no vaccines or treatments have been developed, a genetically based approach could be an innovative strategy to prevent and to control SRLVs infection. Our findings are an important starting point in order to define the genetic resistance profile towards SRLVs infection.