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Abstract Background The potent immune effects of interleukin‐2 (IL‐2) for cancer therapy can be increased by genetic fusion of IL‐2 to the Fc domain of an antibody (IL‐2‐Fc) or tumor targeted by genetic fusion to a whole antibody known as an immunocytokine (ICK). Methods An anti‐CEA ICK (M5A‐IL‐2) was compared to an IL‐2‐Fc fusion protein using tumor therapy and PET imaging in CEA transgenic immunocompetent mice bearing CEA positive colon or breast tumors. Combination with stereotactic radiation therapy (SRT) was performed with either ICK or IL‐2‐Fc. Results ICK and IL‐2‐Fc had comparable antitumor effects in both tumor models, although ICK had higher tumor uptake and slower blood clearance than an IL‐2‐Fc. Analysis of IFNγ+/CD8+ and FoxP3+/CD4+ T cells revealed higher levels of IFNγ‐producing CD8+ T cells in ICK treated mice versus more efficient Treg elimination in IL‐2‐Fc treated mice. No significant or lasting toxicity was detected for either agent. Combination therapies with SRT revealed comparable efficacy and induction of immune memory for both ICK and IL‐2‐Fc when mice were rechallenged post‐therapy. Conclusions IL‐2‐Fc had comparable antitumor efficacy to CEA‐targeted M5A‐IL‐2 ICK, while both fusion proteins induced immune memory when combined with SRT. Differences in the therapeutic mechanisms of both agents were observed.