The polymorphic loci of the bovine prion protein (PRNP) gene, comprising 23-bp insertion/deletion (23-bp indel) within the promoter sequence and 12-bp insertion/deletion (12-bp indel) within the intron 1 sequence, are located in regions which play a key role in gene expression. The objective of this study was to determine whether the 23-bp and 12-bp insertion/deletion polymorphism within the PRNP gene leads to significant differences in the blood lymphocyte profile and to investigate changes in the composition of these cells in cattle naturally infected with Bovine Leukemia Virus. An analysis of the effect of the bovine PRNP gene polymorphism on the blood lymphocyte profile revealed considerable differences between animals with the 23-bp indel genotypes, and small and statistically non-significant differences between those with the 12-bp indel genotypes. 23-bp del/del homozygotes had a significantly lower percentage of T lymphocytes with the phenotypes CD2 (P < 0.01), CD8 (P < 0.01) and WC1-N2 (P < 0.05), and a higher ratio of CD4 to CD8 T lymphocytes, compared to animals with the 23-bp ins/ins genotype. The obtained results indicate that the 23-bp indel polymorphism, in contrast to the 12-bp indel polymorphism, has a significant effect on changes in the blood lymphocyte profile. The size of blood lymphocyte subpopulations was also found to change under the influence of enzootic bovine leukosis. The direction of those changes in EBL-positive animals is consistent with that observed in 23-bp del/del homozygotes, which may testify to the adverse effect of this genotype on immunological efficiency.