There is much evidence suggesting that the decline in ovarian function after menopause is associated with spontaneous increases in proinflammatory cytokines. Treatment with risedronate is accompanied by significant changes in bone turnover and bone mineral density. The objective of this study was to determine the effects of risedronate treatment on the level of serum cytokines including receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin among postmenopausal women with osteoporosis. The study group consisted of 61 postmenopausal women with osteoporosis. Patients were randomly divided in two groups: In group 1 (n = 41) postmenopausal women received oral risedronate (35 mg/week), calcium (1,000 mg/day), and vitamin D (400 IU/day) for 12 months. In group 2 (control group; n = 20) patients received only oral calcium (1,000 mg/day) and vitamin D (400 IU/day). Bone mineral density (BMD) of lumbar spine (L1-L4) and proximal femur were determined using dual X-ray absorptiometry at baseline and after one year. Venous blood samples were obtained for determination of serum cytokines including interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), RANKL, osteoprotegerin, and markers of bone formation and resorption. Levels of serum cytokines were measured before therapy and after three and 6 months. Markers of bone metabolism were studied before therapy and after 6 months. In group 1 (risedronate plus calcium/vitamin D-treated patients), serum levels of RANKL and IL-1beta significantly decreased and the level of osteoprotegerin significantly increased after three and 6 months, but no significant difference was found in TNF-alpha level. In group 2, however, the level of serum cytokines did not change after three and 6 months. In cases of bone turnover, both markers of bone resorption and formation significantly decreased after 6 months in group 1. In conclusion risedronate could improve osteoporosis by increasing osteoprotegerin and reducing RANKL and IL-1beta.