STATs (signal transducers and activators of transcription) are transcription factors that contain SH2 domains and are activated by tyrosine phosphorylation in response to cytokines and growth factors. Replication protein A (RPA) is a heterotrimeric complex that consists of three subunits, p70, p32 and p11, and has important functions in DNA replication and metabolism. Here, I present evidence that the RPA p32 subunit specifically binds to the SH2 domain of STAT3 in a phosphotyrosine-independent manner. I confirm their protein-protein interactions by yeast 2-hybrid analyses and in vitro binding assays using recombinant proteins generated from bacteria and in vitro translation. I also show that STAT3 binds to RPA p32 in vivo by conducting co-precipitation experiments. As the SH2 domain is highly involved in the tyrosine phosphorylation and the transcriptional activity of STAT3, over-expression of RPA p32 correspondingly augmented growth factor-stimulated tyrosine phosphorylation and transcription activities of STAT3.