The existence of a tradeoff between the reproductive success and immunity was demonstrated in the works conducted on wild and laboratory animals. Therefore, individuals with an increased reproductive capacity but with decreased immunity could be selected in the process of domestication. A decreased reactivity of the immune system could subsequently become inheritable by fixation of the genes with unfavorable mutations in the population. The aim of the investigation was to study (1) the genotype and allele frequencies of the rs340283541 single nucleotide polymorphism (SNP) in the lymphotoxin beta (LTB) cytokine gene in domestic pigs and wild boars; (2) the mRNA expression for this gene in mini pigs with different genotypes; and (3) to perform the bioinformatic analysis of a potential functional role of this SNP. The GG genotype frequency in the boar sample was significantly lower than this genotype frequency in the combined sample from different domestic pig breeds and populations. The level of the LTB gene mRNA expression in a lymph node in mini pigs with GG genotype had a trend towards an increase (p < 0.06) as compared with the A allele carriers. The rs340283541 SNP is located within the conservative sequence motif revealed in 12 mammalian species (that indirectly indicates important functional role of SNP). By means of the context analysis, it was detected that the A allele contains potential binding sites for the BRN-2 and AP-1 transcription factors, while the G allele contains those for the RFX1, ISGF3 (ISRE site), and USF (that are expressed in the immune system cells). Thus, an increase in the frequency of the rs340283541 SNP (located in the LTB gene 3'-region) GG genotype occurred in the process of pig domestication. The GG genotype is probably associated with an increased level of the LTB gene mRNA expression in the lymph node tissue. An increase in the expression level in pigs with the GG genotype can be associated with generation of the RFX1, ISRE, and USF binding sites and/or damage of the BRN-2 and AP-1 binding sites. It is also possible that the rs340283541 polymorphism is in linkage disequilibrium with another functionally significant mutation.