The widely shared enthusiasm about the cardioprotective potential of estrogenic compounds has come to an abrupt halt since randomized trials failed to show a cardiovascular risk reduction in postmenopausal women. This was unexpected because observational studies had strongly suggested that hormone replacement therapy would reduce the incidence of cardiovascular disease. Inflammatory activity is considered central in atherogenesis and atherosclerosis progression. Thus, parts of the striking discrepancy between observational and randomized data have been attributed to an estrogen-mediated adverse effect on inflammation. Here, we review the current clinical evidence with respect to the inflammation-modulating effects of different estrogenic compounds as one potential explanatory factor for these divergent findings. We conclude that it is still unclear whether estrogen-modulated inflammation is an important biological factor determining clinical outcome or a mere epiphenomenon.