Tumor-associated macrophages (TAMs) appear to be the major component in solid tumor microenvironment, which were reported to play an important role in tumor malignant progression. Recently, TAMs were reported to be associated with drug resistance in some types of solid tumor including breast cancer. However, how TAMs regulate breast tumor resistance remains unknown. In this study, THP-1 cells were stimulated with PMA and IL-4/IL-13 to form M2-like macrophages to study the role of TAMs on chemoresistance. Our results showed that TAMs and its supernatants significantly prevent breast tumor cells from apoptosis caused by paclitaxel. We also found that the high level of IL-10 secreted by TAMS was responsible for drug resistance of breast cancer. The possible TAMs-modulated drug resistance mechanism involved may be associated with elevation of bcl-2 gene expression and up-regulation of STAT3 signaling in tumor cells. Furthermore, the blockage of TAMs-derived IL-10 by neutralizing antibody resulted in attenuation of STAT3 activation and decrease of bcl-2 mRNA expression, consequently enhanced sensitivity of breast cancer cells. Our data suggested that TAMs might induce drug resistance through IL-10/STAT3/bcl-2 signaling pathway, providing possible new targets for breast tumor therapy.