Ectopic activation of fibroblast growth factor receptor 3 (FGFR3) is associated with several cancers, including multiple myeloma (MM). FGFR3 inhibition in these cells inhibits proliferation and induces apoptosis, validating FGFR3 signaling as a therapeutic target in t(4;14) MM cases. We have identified the PI3K regulatory subunit, p85α, as a novel interactor of FGFR3 by yeast two-hybrid, and confirmed an interaction with both p85α and p85β in mammalian cells. The interaction of FGFR3 with p85 is dependent upon receptor activation. In contrast to the Gab1-mediated association of FGFRs with p85, the FGFR3-p85 interaction we observed requires FGFR3 Y760, previously identified as a PLCγ binding site. The interaction of p85 with FGFR3 does not require PLCγ, suggesting the p85 interaction is direct and independent of PLCγ binding. FGFR3 and p85 proteins also interact in MM cell lines which consistently express p85α and p85β, but not p50 or p55 subunits. siRNA knockdown of p85β in MM cells caused an increased ERK response to FGF2. These data suggest that an endogenous negative regulatory role for the p85-FGFR3 interaction on the Ras/ERK/MAPK pathway may exist in response to FGFR3 activity and identifies a novel therapeutic target for MM.