Interleukin-12 (IL-12) is a proinflammatory cytokine that links innate and adaptive immune responses against tumor cells. Single Nucleotide Polymorphisms (SNPs) in IL-12 genes have been associated with cancer risk. However, limited studies have assessed the role of IL-12 in breast cancer (BC) risk comprehensively, and these were done in European and Asian populations. Here, we evaluated the association of the IL-12 signaling pathway and BC risk in Puerto Rican women. A genetic association study was completed with 461 BC cases and 463 non-BC controls. By logistic regression, IL-12 signaling SNPs were associated with an increased BC risk, including rs2243123 ( IL12A ), rs3761041, rs401502 and rs404733 ( IL12RB1 ), rs7849191 ( JAK2 ), rs280500 ( TYK2 ) and rs4274624 ( STAT4 ). Conversely, other SNPs were associated with reduced BC risk including rs438421 ( IL12RB1 ), rs6693065 ( IL12RB2 ), rs10974947, and rs2274471 ( JAK2 ), rs10168266 and rs925847 ( STAT4 ), and rs2069718 ( IFNG ). Analyses based in hormone receptors such as estrogen (ER) and progesterone (PR) receptors also revealed protective (for SNPs rs3212227- IL12B ; rs3024896 and rs3821236- STAT4 ) and predisposing (for rs2069705- IFNG SNP) BC associations. Haplotype analysis showed a decreased BC risk for IL12B and STAT4 SNPs, whereas increased risk for IL12RB1 SNPs . This study suggests a role of the IL-12 signaling axis and BC risk. SNPs in this pathway may alter IL-12 induced anti-tumor responses and modulate BC predisposition in a population-specific context. Functional studies will be necessary to confirm these findings, which potentially may benefit IL-12 related immunotherapeutic approaches towards BC.