Complex regional pain syndrome (CRPS) Type I, also known as reflex sympathetic dystrophy (RSD), usually develops after trauma or immobilization, is characterized by focal pain and autonomic dysregulation, and sometimes focal trophic changes such as osteoporosis. The pathophysiology is unknown and there have been few controlled treatment trials. Small trials with alendronate, pamidronate, and clodronate suggest that bisphosphonates may be effective. Their mode of action in this condition is unknown, but might be related to their inhibition of osteoclast activity or anti-inflammatory activity. To further evaluate the role of bisphosphonates, we conducted a pilot trial of ibandronate, a highly potent bisphosphonate. After a 2-week baseline period, 10 patients with CRPS received three 6-mg-infusions during week3, and were followed from weeks 4-7. Aside from transitory flu-like symptoms, the drug was well tolerated. Post-intervention average and worst pain ratings were significantly improved over baseline (P=0.0065, 0.0036, respectively); as were several neuropathic pain descriptors: unpleasantness, sensitivity, depth (all Ps≤0.005); intensity, surface, heat (all Ps≤0.01); cold, sharpness, dullness (all Ps≤0.03). Subjects with baseline bone scans showing greater tracer uptake in the affected limb (compared to unaffected limb), improved more than those having decreased uptake in the heat, cold, sensitivity, and unpleasantness neuropathic pain aspects (all Ps≤0.03). Although univariate analyses indicated subjects with hand RSD improved significantly more than those with leg RSD in average and worst pain, as well as in many neuropathic pain aspects, multivariate analyses indicated greater improvement only in the time aspect of neuropathic time; i.e., they were less likely to have pain ALL OF THE TIME (p=0.0010). While range of motion did not improve, post-intervention, the final physical examination showed a 2-point improvement over baseline in hyperalgesia and allodynia (both Ps<0.005). These data indicate that a placebo-controlled trial is warranted to definitively determine the analgesic efficacy of ibandronate for CRPS.