Pernicious anemia has recently been recognized as a risk factor for osteoporosis and fractures. Although vitamin B12 is important for osteoblast function, the effect of vitamin B12 replacement in states of vitamin B12 deficiency on bone density and fracture incidence is not known. We report 2-year follow-up data from a patient with severe osteoporosis, multiple vertebral compression fractures, and pernicious anemia who exhibited a dramatic response to treatment with vitamin B12 and cyclic etidronate. Serial bone density measurements demonstrated a 15% and 17% increase in the lumbar and greater trochanter regions, respectively, and a 79% increase in the femoral neck region over the 2-year follow-up period. In addition to normalization of bone density compared with age-matched controls, no subsequent vertebral fractures were noted in the 2-year period following initiation of vitamin B12 and etidronate therapy. This case demonstrates that osteoporosis associated with pernicious anemia may be markedly improved by vitamin B12 replacement and cyclic etidronate therapy.