Macrophage inhibitory cytokine-1 (MIC-1), a member of the transforming growth factor-beta superfamily, is important in regulating inflammation. Inflammation of the prostate has been suggested to favor tumor development. A recent study (JNCI 2004, 96:1248-1254) found marginal evidence of an association between the presence of the mature MIC-1 protein nonsynonymous polymorphism H6D C-to-G (rs1058587) with reduced prostate cancer risk [odds ratio, 0.83; 95% confidence interval (95% CI), 0.69-0.99]. We tested this in a population-based study of 819 cases and 731 controls from Australia and found a similar, yet not significant, odds ratio of 0.85 (95% CI, 0.7-1.04; P = 0.11). We also tested the potential association between the H6D variant and disease-specific survival in 640 cases followed-up for an average of 8.2 years. We found that cases carrying the H6D G allele had an increased risk of death from prostate cancer than cases carrying two copies of the C allele (hazard ratio, 1.72; 95% CI, 1.06-2.78; P = 0.03). Our data suggest that the H6D variant in MIC-1 might play a role in prostate cancer, but it is difficult to explain how a variant can be associated with lower risk of developing prostate cancer but more aggressive growth if cancer develops.