The microphthalmia transcription factor/transcription factor E (TFE)-family translocation renal cell carcinomas bear specific translocations that result in overexpression of TFE3 or TFEB. TFE3 fusion gene product overexpression occurs as consequence of different translocations involving chromosome Xp11.2, whereas TFEB overexpression is the result of the specific translocation t(6;11)(p21;q12), which fuses the Alpha gene to TFEB. Both TFE3 and TFEB are closely related members of the microphthalmia transcription factor/TFE-family, which also includes TFEC and microphthalmia transcription factor. These transcription factors have overlapping transcriptional targets. Overexpression of microphthalmia transcription factor has been shown to mediate the expression of cathepsin-K in osteoclasts. We hypothesize that the overexpression of the related TFE3 fusion proteins and TFEB in translocation renal cell carcinomas may have the same effect. We studied cathepsin-K in 17 cytogenetically confirmed microphthalmia transcription factor/TFE-family translocation renal cell carcinomas. Seven cases showed a t(6;11)(p21;q12), ten cases showed translocations involving Xp11.2; five cases t(X;1)(p11;q21) resulting in a PRCC-TFE3 gene fusion; three cases t(X;1)(p11;p34) resulting in a PSF-TFE3 gene fusion, one t(X;17)(p11;q25) resulting in an ASPL-TFE3 gene fusion, and one t(X;3)(p11;q23) with an unknown TFE3 gene fusion. As control we analyzed cathepsin-K in 210 clear cell, 40 papillary, 25 chromophobe renal cell carcinomas and 30 oncocytomas. All seven TFEB translocation renal cell carcinomas were labeled for cathepsin-K. Among the cytogenetically confirmed TFE3 translocation renal cell carcinomas, 6 out of 10 were positive. None of the other renal neoplasms expressed cathepsin-K. We conclude the following: (1) cathepsin-K is consistently and strongly expressed in TFEB translocation renal cell carcinomas and in 6 of 10 TFE3 translocation renal cell carcinomas. (2) Cathepsin-K immunolabeling in both TFE3 and TFEB translocation renal cell carcinomas distinguishes these neoplasms from the more common adult renal cell carcinomas, and may be a specific marker of these neoplasms. (3) These results further support the concept that the overexpression of TFE3 or TFEB in these neoplasms activates the expression of genes normally regulated by microphthalmia transcription factor in other cell types. © 2009 USCAP, Inc.