The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is involved in immune function and cell growth; genetic variation in this pathway could influence breast cancer risk. We examined 12 genes in the JAK/STAT/SOCS signaling pathway with breast cancer risk and mortality in an admixed population of Hispanic (2,111 cases, 2,597 controls) and non-Hispanic white (1,481 cases, 1,585 controls) women. Associations were assessed by Indigenous American (IA) ancestry. After adjustment for multiple comparisons, JAK1 (three of ten SNPs) and JAK2 (4 of 11 SNPs) interacted with body mass index (BMI) among pre-menopausal women, while STAT3 (four of five SNPs) interacted significantly with BMI among post-menopausal women to alter breast cancer risk. STAT6 rs3024979 and TYK2 rs280519 altered breast cancer-specific mortality among all women. Associations with breast cancer-specific mortality differed by IA ancestry; SOCS1 rs193779, STAT3 rs1026916, and STAT4 rs11685878 associations were limited to women with low IA ancestry, and associations with JAK1 rs2780890, rs2254002, and rs310245 and STAT1 rs11887698 were observed among women with high IA ancestry. JAK2 (5 of 11 SNPs), SOCS2 (one of three SNPs), and STAT4 (2 of 20 SNPs) interacted with cigarette smoking status to alter breast cancer-specific mortality. SOCS2 (one of three SNPs) and all STAT3, STAT5A, and STAT5B SNPs significantly interacted with use of aspirin/NSAIDs to alter breast cancer-specific mortality. Genetic variation in the JAK/STAT/SOCS pathway was associated with breast cancer-specific mortality. The proportion of SNPs within a gene that significantly interacted with lifestyle factors lends support for the observed associations.