Clinical mastitis cows normally produce clotted milk, thus the much higher somatic cells in milk are unable to be counted by routine FOSS machine. The proteins coded by CD4 and LAG-3 genes can bind to MHC class II molecules and play important roles in in-flammatory diseases. The present study was designed to investigate the effects of single nucleotide polymorphisms (SNPs) in bovine CD4 and LAG-3 genes on the somatic cell counts (SCCs) of clinical mastitis Holstein cows. For the first time, we detected SCCs in the clinical mastitis cows’ milk by Newman’s staining combined with microscope assays. Our association results showed that two novel SNPs (T104010752C and C104028410T) identified in bovine CD4 and LAG-3 genes respectively were significantly associated with SCCs of clinical mastitis cows (P<0.05). In addition, the combined genotypic effect of both the SNPs was also significant on SCCs (P<0.05). The results imply that the novel SNPs in CD4 and LAG-3 genes could be significant candidate markers against Clinical mastitis in Holstein cattle.