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Controlled-release, injectable polymer microspheres provide a clinically feasible alternative to gene-modification for the local, sustained delivery of cytokines to tumors for cancer immunotherapy. Long-term release kinetics, bioactivity profiles, and stability of interleukin-2 (IL-2), interleukin-12 (IL-12), and granulocyte- macrophage colony-stimulating factor (GM-CSF)-encapsulated microspheres prepared by phase inversion nanoencapsulation (PIN) were evaluated. While all formulations released physiologically relevant quantities of cytokine for up to 30 days, the individual release kinetics were different. Recovery of specific activity after encapsulation was 40%, 60%, and 90%-that of pre-encapsulation levels for IL-2, GM-CSF and IL-12, respectively. Upon storage, the IL-12 microspheres rapidly lost activity, whereas IL-2 and GM-CSF microspheres remained stable for at least 9 weeks. These studies demonstrate that biochemical properties of microsphere formulations vary depending on the cytokine, and rigorous characterization of formulations is a prerequisite to in vivo testing.