Bisphosphonates have significantly improved the treatment of postmenopausal osteoporosis. However, when administered orally, gastric intolerance is their main adverse effect. This makes patients reluctant to undergo treatment. As an alternative, intramuscular (i.m.) administration may be more acceptable to patients undergoing long-term treatment. Since clodronate has been easily available in Italy for many years, we carried out this study to evaluate its effect on bone mineral density (BMD) in 36 osteoporotic postmenopausal women who were intolerant to oral administration of bisphosphonates. Patients received 100 mg of clodronate i.m. every 10 days together with 500 mg/day of calcium orally for 2 years. A control group of 32 women received only oral calcium at the same dose and for the same length of time. In the control group a progressive but not statistically significant decrease in BMD was observed in the spine and femoral neck over the 2-year follow-up. In contrast, patients treated with clodronate had a statistically significant increase in BMD in the spine at the first yearly check-up (+2.63%) and a further but not statistically significant increase during the second year of treatment (+0.59%). The increase in BMD at the femoral neck was not statistically significant during the first and second years of treatment, being 1.21% and 0.37% respectively. In the women treated with clodronate, hydroxyproline was significantly suppressed. All the patients reported local pain at the injection site. This led 11.11% of the subjects to withdraw from treatment.