The Saccharomyces cerevisiae protein, Set2, has recently been shown to be a histone methyltransferase. To elucidate the function of Set2, its associated proteins were identified using tandem affinity purification and mass spectrometry. We found that Set2 associates with RNA polymerase II. The interaction between the Set2 protein and RNA polymerase II requires the WW domain in Set2 and phosphorylation of the carboxyl-terminal domain of the largest subunit of RNA polymerase II. Set2 directly binds to the carboxyl-terminal domain with phosphorylated Ser(2) in the heptapeptide repeats. set2 deletion mutant is sensitive to 6-azauracil, a property often associated with impaired transcription elongation. Together, our results suggest that Set2 through association with the elongating form of RNA polymerase II plays an important role in transcription elongation.