Previous studies have implicated estrogen as a regulator of epidermal growth factor receptor (EGFR) expression in breast tumors. We therefore speculated that estrogen might modulate serologic soluble EGFR (sEGFR) concentrations in breast cancer patients. Accordingly, we measured serum sEGFR concentrations in postmenopausal women with metastatic breast cancer (MBC) treated with letrozole, an aromatase inhibitor that blocks estrogen synthesis. Serum specimens were obtained prior to and following 1 and 3 months of letrozole therapy. We report that sEGFR concentrations do not differ between MBC patients prior to letrozole treatment and age- and postmenopause-matched healthy women (P = 0.468). In contrast, however, sEGFR concentrations decreased significantly in 76% of MBC patients after both 1 month (P = 0.006) and 3 months (P = 0.003) of letrozole therapy versus pretreatment concentrations. Within the limitations of this study, we found no evidence for an association between pretreatment sEGFR concentrations or decreased treatment sEGFR concentrations and either progression-free or overall survival. Nonetheless, we conclude that future prospective studies are warranted to determine if baseline and/or longitudinal serum sEGFR concentrations may be useful for predicting disease progression and survival, and/or for monitoring responsiveness to aromatase inhibitors or other endocrine therapies in breast cancer patients.