Rodent models suggest that estradiol deficiency promotes bone loss through increasing interleukin-6 (IL-6) activity. However, it is controversial as to whether these findings are applicable to humans. To evaluate estradiol-mediated modulation of IL-6 activity in relation to bone metabolism in humans, we measured serum IL-6, soluble interleukin-6 receptor (sIL-6R), estradiol (E2), progesterone, luteinizing hormone, follicle-stimulating hormone, intact parathyroid hormone (PTH), serum and urine Ca, and bone biochemical markers (serum bone-specific alkaline phosphatase, osteocalcin, and serum and urine deoxypyridinoline [Dpd]) across one menstrual cycle for 211 women. Neither IL-6 nor sIL-6R levels differed between the follicular phase (FP) and the luteal phases (LP). However, IL-6 was negatively correlated with E2 during the FP (p =0.003). Furthermore, IL-6 correlated positively with serum Ca over the entire cycle (p = 0.0091. Serum Ca correlated positively with serum (p = 0.040) and urine (p = 0.006) Dpd. PTH was significantly higher during the FP than in the LP (p = 0.004). PTH was negatively related to E2 (p = 0.002), serum Ca (p < 0.001), and urine Ca (p = 0.036), whereas it was positively correlated with IL-6 (p = 0.027). These data demonstrate that IL-6 and PTH fluctuate with E2, and serum II-6 is associated with PTH levels during the menstrual cycle. However, the role of 11-6 in bone remodeling during the normal menstrual cycle remains to be determined.