In cancer therapy novel concepts focus on phosphoinositide 3-kinase (PI3K)/activated protein kinase B (p-AKT)/mammalian target of rapamycin (mTOR) inhibitors. In this context, p-AKT overexpression was previously shown to be associated with sensitivity to inhibitors of mTOR. The present study evaluated p-AKT expression in a tissue microarray of primary renal cell carcinomas (PRCCs) (n = 45), their metastases (primary onset n = 45, secondary onset n = 5), and normal renal parenchyma (n = 45) by means of immunohistochemistry. Total p-AKT overexpression was found in 24/45 (53.3%) PRCCs, in 32/45 (71.1%) primary and in 3/5 (60%) secondary onset metastases. Membranous p-AKT overexpression was seen more frequently in PRCCs, namely 11/45 (24.4%), than in primary onset metastases 1/45 (2.2%). Overexpression of total p-AKT solely in metastases without overexpression in PRCC was exclusively demonstrated in primary onset metastases, namely in 28.9%. Patients with total p-AKT overexpression in primary carcinomas showed a trend to longer, and those with total p-AKT overexpression in metastases a tendency to shorter survival. In conclusion, the present study shows total p-AKT overexpression to be more frequent in metastases than in PRCCs. Total p-AKT overexpression in metastases without concomitant overexpression in their primary tumors was found in approximately one-third of primary onset metastases, which is interesting with regard to the association between high p-AKT expression and sensitivity to mTOR inhibitor therapy.