Objectives: To compare the effect of a single infusion of zoledronic acid (ZA) with placebo on knee pain and bone marrow lesions (BMLs). Methods: Adults aged 50-80 years (n=59) with clinical knee osteoarthritis and knee BMLs were randomised to receive either ZA (5 mg/100 ml) or placebo. BMLs were determined using proton density-weighted fat saturation MR images at baseline, 6 and 12 months. Pain and function were measured using a visual analogue scale (VAS) and the knee injury and osteoarthritis outcome score (KOOS) scale. Results: At baseline, mean VAS score was 54 mm and mean total BML area was 468 mm 2. VAS pain scores were significantly reduced in the ZA group compared with placebo after 6 months (-14.5 mm, 95% CI -28.1 to -0.9) but not after 3 or 12 months. Changes on the KOOS scales were not significant at any time point. Reduction in total BML area was greater in the ZA group compared with placebo after 6 months (-175.7 mm 2, 95% CI -327.2 to -24.3) with a trend after 12 months (-146.5 mm 2, 95% CI -307.5 to +14.5). A greater proportion of those in the ZA group achieved a clinically significant reduction in BML size at 6 months (39% vs 18%, p=0.044). Toxicity was as expected apart from a high rate of acute phase reactions in treatment and placebo arms. Conclusions: ZA reduces knee pain and areal BML size and increases the proportion improving over 6 months. Treatment of osteoarthritis may benefit from a lesion specific therapeutic approach. Clinical trial registration number: ACTRN 12609000399291.