The KRT19 gene encodes cytokeratin 19, an element of the cytoskeleton whose expression is frequently altered in renal cell carcinoma (RCC). Epigenetic phenomena, such as promoter methylation, may be a regulatory mechanism of expression of this gene. The aim of this study was to assess the epigenetic regulation of the KRT19 gene using epigenetic-modulating drugs, through the evaluation of methylation and expression status of the promoter region of KRT19 in 6 renal carcinoma cell lines and 112 primary renal tumors (52 clear cell RCC, 22 papillary RCC, 22 chromophobe cell RCC, and 16 oncocytomas). The diagnostic and prognostic value of KRT19 methylation levels in RCC was also evaluated. In cell lines 769-P, A498, and Caki-1, KRT19 re-expression was observed after treatment with 5-aza-2'deoxycytidine and trichostatin A. Conversely, a decrease in promoter methylation levels was apparent for the same cell lines. In primary renal tumors, KRT19 promoter methylation frequency was low (20.5% of cases). Although chromophobe cell RCC showed the lowest frequency compared with the remaining subtypes, this difference did not reach statistical significance. Moreover, no correlation between KRT19 methylation and expression was apparent in tumor samples and no significant correlations with clinicopathological parameters were observed. KRT19 methylation is not a frequent feature of primary RCC and oncocytomas, nor is it associated with clinicopathological parameters. Although we found evidence that KRT19 gene expression is epigenetically regulated in cell lines, this finding was not translated to primary tumors, suggesting the intervention of other genetic mechanisms for in vivo regulation of the KRT19 gene.