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Alterations of the respiratory chain and mutations of the mitochondrial DNA (mtDNA) have been extensively investigated in a wide variety of neoplasias. However, no obvious correlation of a certain type of tumor and mtDNA mutations has been reported so far. I compared both, enzymatic measurements of the respiratory chain and mtDNA mutations in renal carcinomas and renal oncocytomas. To enable a high throughput screen of mtDNA variations, I developed a DHPLC-based protocol for a rapid detection of unknown variations of the entire human mtDNA. The benign renal oncocytomas were in clear contrast to the malign renal carcinomas. The oncocytomas showed significantly increased Krebs cycle- and OXPHOS enzyme activities, except a total breakdown of the complex I enzyme activity. The mutation screening revealed frame shift mutations, encoding mitochondrial ND genes in 8 out of 12 oncocytomas. All these somatic frame shift mutations displayed a homoplasmy of 100%. This study shows for the first time a direct correlation of mtDNA mutations in a specific type of cancer, which leads to a total lack of complex I enzyme activity in the respiratory chain.