The present study investigated the interaction between Cdx-2 polymorphism and physical activity level over bone mineral density (BMD) variation in Brazilian postmenopausal women. One hundred and ninety women volunteered to participate in the study (66.6 +/- 5.3 years, 64.58 +/- 11.74 kg and 151.94 +/- 6.36 cm). Physical activity level (PAL) was assessed using the international physical activity questionnaire (IPAQ). Lumbar spine (L2 - L4), femoral neck, great trochanter and Wards' triangle bone mineral density (BMD) were measured by dual-energy X-ray absorptiometry (DXA). The Cdx-2 polymorphism was genotyped by minisequencing, using the SNaPshottrade mark Multiplex System (Applied Biosystems, Foster City, CA, USA). Overall, no significant association was found between Cdx-2 polymorphism and adjusted BMD at any site. However, the results revealed a significant interaction between PAL and Cdx-2 genotype on adjusted femoral neck and Wards' triangle BMD. Active women carrying the Cdx-G/G genotype showed higher adjusted femoral neck and Wards' triangle BMD than inactive women carrying the same genotype, thus suggesting a larger chronic response to physical activity. These results suggest that, in postmenopausal women, the Cdx-2 polymorphism does not influence BMD by itself; however, it seems to affect the BMD response to physical activity since only the Cdx-G/G genotype carriers presented significant differences between active and inactive.