Macrophage-inhibitory cytokine-1 (MIC-1) is a divergent member of the transforming growth factor β superfamily. It is up-regulated by nonsteroidal anti-inflammatory drugs and is highly expressed in human prostate cancer leading to high serum MIC-1 concentrations with advanced disease. A role for MIC-1 has been implicated in the process of early bone formation, suggesting that it may also mediate sclerosis at the site of prostate cancer bone metastases. Consequently, the aim of this study was to retrospectively determine the relationship of serum MIC-1 concentration and other markers related to current and future prostate cancer bone metastasis in a cohort of 159 patients with prostate cancer. Serum markers included cross-linked carboxy-terminal telopeptide of type I collagen, prostate-specific antigen, and amino-terminal propeptide of type I procollagen (PINP). The mean values of all the biomarkers studied were significantly higher in patients with baseline bone metastases (BM+, n = 35), when compared with those without bone metastases (BM-, n = 124). In a multivariate logistic model, both MIC-1 and PINP independently predicted the presence of baseline bone metastasis. Based on receiver operator curve analysis, the best predictor for the presence of baseline bone metastasis was MIC-1, which was significantly better than carboxy-terminal telopeptide of type I collagen, prostate-specific antigen, and PINP. Patients who experienced bone relapse had significantly higher levels of baseline MIC-1 compared with patients who did not (1476.7 versus 988.4; P = 0.03). Current use of acetylsalicylic acid did not influence serum MIC-1 levels in this cohort. Although requiring validation prospectively, these results suggest that serum MIC-1 determination may be a valuable tool for the diagnosis of current and future bone metastases in patients with prostate cancer. Copyright © 2007 American Association for Cancer Research.