Herpesvirus saimiri (HVS) is an oncogenic gamma-2 herpesvirus that causes lymphoma in New World primates. HVS can be further divided into subgroups A, B, and C, based on sequence divergence. Saimiri transforming protein (STP) is coded for by the first open reading frame at the left end of the HVS genome and is responsible for its oncogenic potential. Here we show that STP A11 binds to signal transducers and activators of transcription 3 (STAT3), stimulates STAT3 phosphorylation, and activates STAT3-dependent transcription. STP A11 recruited c-Src kinase to phosphorylate STAT3 protein, and co-expression of STP A11 with c-Src dramatically increased STAT3 phosphorylation. We found that the amino terminal domain of STP A11 is required for both STAT3 interaction and activation, and that physical interaction is required for STAT3 activation. (C) 2004 Elsevier Inc. All rights reserved.