Renal carcinogenesis is promoted by overexpression of the activated serine/ threonine kinase Akt (p-Akt) and supposedly a concomitant reduction in phosphatase and tensin homologue deleted on chromosome 10 tumour suppressor gene (PTEN), which normally inhibits the activation of Akt. Because promising anti-cancer therapies increasingly focus on pathways involving p-Akt and PTEN, the present study evaluated the expression of p-Akt in renal cell carcinomas and compared it with prognosis. P-Akt and PTEN expression were analysed in a tissue microarray (TMA) from renal cell carcinoma (n = 386) and adjacent uninvolved renal tissue (n = 32) specimens. Increased p-Akt was found more often in the nucleus than in the cytoplasm, and PTEN was concomitantly reduced in about 50% of cases. Neither tumour grade nor stage influenced p-Akt expression, whereas the clear cell and papillary subtypes showed increased p-Akt more often than did the chromophobe or sarcomatoid types. Increased cytoplasmic and nuclear p-Akt levels were independent prognostic factors for diminishing patient survival. The present study found significantly increased nuclear but also cytoplasmic p-Akt expression in renal cell carcinoma subtypes. Increased nuclear and cytoplasmic p-Akt was an independent prognostic factor for diminishing patient survival. The considerable number of high-grade and high-stage RCC showing increased p-Akt and reduced PTEN would justify further evaluation of therapeutic concepts based on inhibitors of the PI3K/p-Akt/mTOR pathway.