The genetic or abnormal activation of signal transducer and activator of transcription (STATs) family proteins play an important role with regard to disease progression in variety of human malignancies, yet no data are available for candidate gene and breast cancer (BC) risk. To address this, we investigate the correlation between STAT3, STAT5b polymorphisms and BC susceptibility, clinicopathological parameters, and clinical outcomes. A case-control study was carried out in 1,240 BC patients and 882 healthy controls using TaqMan assay and PCR-RFLP method. A significant decreased risk of BC was associated with STAT3 G allele and combined effect (validation alleles). Furthermore, patients after anthracycline-based chemotherapy, carrying combined effect of STAT3 rs4796793 and STAT5b rs6503691, had significantly increased progression-free survival (PFS) [adjusted HR (95 % CI) 0.831 (0.704-0.980), P = 0.028]. More importantly, ER-negative patients with STAT5b CT/TT genotype was associated with a longer PFS [adjusted HR (95 % CI) 0.519 (0.293-0.920), P = 0.025], recurrence-free survival [adjusted HR (95 % CI) 0.529 (0.298-0.939), P = 0.030], and overall survival [adjusted HR (95 % CI) 0.547 (0.308-0.973), P = 0.040]. These results indicated that STAT3 and STAT5b polymorphisms might be a candidate pharmacogenomic factor to assess susceptibility and prognosis in BC patients.