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Impending pathologic fractures or spinal cord compressions must have been controlled by surgery or radiation therapy before enrollment. Zoledronate (4 mg) was given intravenously every 4 weeks, thalidomide (300 mg) was given orally once a day, and interferon\u2010\u03b3 (100 \u03bcg) was given subcutaneously once a week. Patients were evaluated for time to skeletal\u2010related events, the appearance of calcification in osteolytic metastases, and levels of the bone formation\/resorption markers.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS.<\/jats:title><jats:p>Fifteen patients were treated between November 2002 and November 2003; 12 had previously undergone surgery, radiation, or embolization for their bone metastases; 11 had more than 3 sites of bone involvement; and 9 also had nonosseous metastases in the lung, liver, lymph node, pancreas, or adrenal gland. The median time to progression was 8.3 weeks (range, 2.1\u201348 weeks). The median time to a skeletal\u2010related event was 12.0 weeks (range, 3.9\u201346.4 weeks). Two patients discontinued treatment because of adverse drug reactions (1 deep venous thrombosis and 1 myocardial infarction). Two patients experienced pain improvement and developed calcification in osseous metastases; these patients also showed favorable changes in bone marker levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS.<\/jats:title><jats:p>In this pilot study a bone\u2010targeted regimen combining zoledronate, thalidomide, and interferon\u2010\u03b3 was well tolerated and might provide clinical benefit for a small subset of patients with renal cell carcinoma and bone metastases. 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