The mouse nuclear receptor ERRγ (estrogen receptor-related receptor γ) is highly expressed in heart, skeletal muscle, kidney, and brain, as well as in the developing nervous system. We found that the expression of the coactivators PGC-1 (PGC-1α) and PERC (PGC-1β) in mammalian cells augmented potently the transcriptional activation by ERRγ. The constitutive activation function 2 (AF-2) of the orphan receptor was important for the synergistic enhancement. Functional receptor truncation analysis revealed an additional amino-terminal activation function, specific for the ERRγ2 isoform and PGC-1. In vitro experiments showed a direct interaction of ERRγ with both coactivators. Our findings suggest distinct regulatory functions for PGC-1 and PERC as tissue-specific coactivators for ERRγ.