Background: Adipokines produced by adipose tissue are directly linked to obesity and may contribute to the pathogenesis of cancer. We hypothesized that genetic and epigenetic modifications in the adiponectin (ADIPOQ) gene and their impact on serum ADIPOQ levels may participate in increasing breast cancer (BC) risk. The present study aimed to investigate ADIPOQ +45 T/G gene polymorphism, methylation status at CpG sites −74 nucleotides (nt) and −283 nt of the ADIPOQ gene, and ADIPOQ serum levels in BC obese women. Methods: Serum ADIPOQ was measured by an enzyme‐linked immunosorbent assay. ADIPOQ +45 T/G gene polymorphism and ADIPOQ promoter methylation status were determined using a polymerase chain reaction (PCR) and a methylationspecific PCR, respectively, in 120 obese women with BC and 120 age‐matched controls. Results: ADIPOQ +45 GG genotype carriers had a significant increased risk of developing BC (odds ratio = 6.2, 95% confidence interval = 1.3–29.6, p = 0.02). ADIPOQ gene methylation at site −74 nt resulted in a 1.7‐fold increased BC risk. Methylation at site –283 nt resulted in a 1.9‐fold increased BC risk. Moreover serum levels of ADIPOQ were significantly decreased in BC patients and down‐regulated in the presence of methylation in both examined sites. By contrast, no association between ADIPOQ gene polymorphism and serum ADIPOQ level was detected. Using both methylated sites in one panel detected cancer breast with 76.67% sensitivity and 62.18% accuracy. Conclusions: ADIPOQ +45 T/G polymorphism and ADIPOQ promoter methylation were found to be associated with BC risk in obese Egyptian women.