Objective. To study the effect of zoledronic acid (ZA) on synovial inflammation, structural joint damage, and bone metabolism in rats during the effector phase of collagen-induced arthritis (CIA). Methods. CIA was induced in female dark agouti rats. At the clinical onset of CIA, rats were assigned to treatment with vehicle or single subcutaneous doses of ZA (1.0, 10, 50, or 100 μg/kg). Clinical signs in all 4 paws were scored on a daily basis. After 2 weeks, the joints in the hind paws were assessed using plain radiographs, microfocal computed tomography (micro-CT), histologic scoring, and histomorphometry, and the serum levels of type I collagen crosslinks were measured by enzyme-linked immunosorbent assay. Results. Although ZA mildly exacerbated synovitis, it effectively suppressed structural joint damage. At doses of ≥10 μg/kg, ZA significantly reduced radio. graphic bone erosions, Larsen scores, and juxtaarticular trabecular bone loss as quantified by micro-CT. ZA prevented increased type I collagen (bone) breakdown in CIA and diminished histologic scores of focal bone erosion by up to 80%. Increases in the percentage of eroded surface, osteoclast surface, and osteoclast numbers associated with CIA were prevented by ZA, even though synovitis scores were unchanged. Conclusion. Single doses (≥10 μg/kg) of ZA strikingly reduced focal bone erosions and juxtaarticular trabecular bone loss, although synovitis was mildly exacerbated. Targeting osteoclasts with ZA may therefore be an effective strategy for preventing structural joint damage in rheumatoid arthritis.