Choline dihydrogen phosphate (CDHP) is a low melting point organic salt reported to increase the thermal stability of model proteins. The purpose of the current work was to investigate the effect of CDHP on recombinant human interleukin-2 (rhIL-2) functional and structural integrity, a therapeutic protein used for treating advanced melanoma. Structural integrity and biological activity of rhIL-2 formulated in CDHP was measured below and above thermal midpoint unfolding temperature (T m) of the protein. Potential biocompatibility was assessed by exposing splenocytes and the B16F10 cell line to CDHP at various concentrations and conditions of pH. Formulation of rhIL-2 in an aqueous 680 mM CDHP pH 7.4 solution preserved rhIL-2 binding activity when the solution was heated to 23.3 °C above T m. CDHP solutions (≤80 mM), formulated with 0.33% (w/v) NaHCO3 to maintain pH ≥ 7.2, exhibited no cytotoxic activity toward primary splenocytes or B16F10 cells cultures. However, a 10-fold loss in biological activity was observed when rhIL-2 was used in a 30 mM CDHP aqueous solution with NaHCO3 (pH ≥ 7.2) compared to controls without CDHP. Choline DHP increases rhIL-2 thermal stability in the absence of inherent CDHP cytotoxicity. While increased T m is associated with a diminished rhIL-2 biological activity, the protein retains binding ability.