Transcriptional downregulation of the putative tumor suppressor gene XIAP-associated Factor 1 (XAF1) by promoter methylation has been shown to relate to tumor progression of gastric and bladder cancer. This study determined the mRNA expression levels and the methylation status of XAF1 by real-time RT-PCR and quantitative methylation specific PCR in tumor tissue obtained from 91 renal cell carcinoma (RCC) patients (median follow-up 50.5 months) following surgical treatment. Expression data was correlated to histopathological variables and outcome. XAF1 expression levels were not related to standard pathological parameters for outcome prediction but results from crude and explorative multivariable-adjusted analyses revealed low XAF1 levels to significantly increase the relative risk (RR) for tumor recurrence (RR 4.6; CI 95%: 1.4-14.6) and tumor-related death (RR 3.6; CI 95%: 1.4-9.7). The association of low XAF1 expression with an abbreviated recurrence-free (p=0.009) and disease-specific survival (p=0.005) was most pronounced in patients with locally advanced (pT3) tumors. XAF1 promoter methylation was rarely detected (10%) but, if present, XAF1 mRNA expression levels correlated inversely to the normalized index of methylation (p=0.01). Our findings suggest that low XAF1 mRNA expression levels relate to an unfavorable clinical course in RCC patients. Promoter methylation may be one, but probably not the essential mechanism for transcriptional downregulation of the XAF1 gene in RCC.