It has been suggested that genetic factors contribute to patients' vulnerability to breast cancer (BC). The programmed cell death 6 interacting protein (PDCD6IP) encodes for a protein that is known to bind to the products of the PDCD6 gene, which is involved in the apoptosis pathway. The aim of this case-control study is to investigate the relationship between the PDCD6IP 15 bp insertion/deletion (I/D) polymorphism (rs28381975) and BC risk in an Iranian population. A total of 491 females, including 266 BC patients and 225 control subjects without cancer, were enrolled into the study. Our findings revealed that the PDCD6IP 15 bp I/D polymorphism decreased the risk of BC in codominant (OR = 0.44, 95% CI = 0.31-0.65, p < 0.0001, I/D versus DD; OR = 0.39, 95% CI = 0.17-0.88, p = 0.030, I/I versus DD) and dominant (OR = 0.44, 95% CI = 0.30-0.63, p < 0.0001, D/I + I/I versus D/D) tested inheritance models. Also, the PDCD6IP I allele significantly decreased the risk of BC (OR = 0.59, 95% CI = 0.45-0.78, p < 0.001) compared to the D allele.