Lytic infection and transformation of cultured cells by JC virus (JCV) require five tumor proteins, which interact with factors regulating critical cellular processes. We demonstrate that JCV large T antigen (TAg) binds the F-box proteins β-transducin-repeat containing protein-1 and 2 (βTrCP1/2). These interactions involve a phosphodegron (DpSGX2–4pS) found in βTrCP substrates. TAg stability is unaltered, suggesting TAg is a pseudo-substrate. βTrCP and TAg co-localize in the cytoplasm, and a functional SCF complex is required. We examined whether TAg influences the levels of β-catenin, a βTrCP substrate. We were unable to demonstrate that TAg elevates β-catenin as previously reported, and a mutant TAg unable to bind βTrCP also had no detectable effect on β-catenin stability. Results presented in this study link JCV TAg to the cellular degradation complex, SCFβTrCP1/2. Proteasomal degradation is essential for proper regulation of cellular functions, and interference with proteasomal pathways highlights possible JCV pathogenic and oncogenic mechanisms.