OBJECTIVE To determine effects of 2 tiludronate administration protocols on measures of lameness in horses with navicular syndrome (NS). ANIMALS 12 horses with bilateral forelimb NS. PROCEDURES Horses were randomly assigned to receive tiludronate (1 mg/kg), diluted in 5 L of isotonic electrolyte solution and delivered through a jugular vein catheter (systemic treatment group; n = 6), or tiludronate (0.1 mg/kg), diluted with saline (0.9% NaCl) solution to a total volume of 35 mL and delivered into the lateral digital vein of each forelimb with an IV regional limb perfusion (IVRLP) technique (IVRLP group; 6). Mean peak vertical ground reaction force (pVGRF) measured with a stationary force plate and subjective lameness scores (SLSs) were recorded before (day −1) and at predetermined time points after tiludronate administration on day 0. Mean pVGRFs (standardized as percentage body weight of force) and mean SLSs for the most lame forelimb and for both forelimbs of horses in each group were compared with day −1 values to determine treatment effect. RESULTS Mean pVGRF for both forelimbs and for the most lame forelimbs of systemically treated horses were significantly increased on days 120 and 200, compared with day −1 results. No significant difference in mean pVGRF was observed for IVRLP-treated horses. The SLSs were not improved at any time point following systemic treatment and were improved only on day 120 following IVRLP. CONCLUSIONS AND CLINICAL RELEVANCE Tiludronate (1 mg/kg, IV) as a single systemic treatment appeared to be beneficial for horses with NS, but no horses were judged as sound during the study period. Additional research on IVRLP with tiludronate is needed before this method can be recommended.