Compelling evidence for naturally occurring immunosurveillance against malignancies informs and justifies some current approaches towards cancer immunotherapy. However, some types of immune reactions have also been shown to facilitate tumor progression. For example, our previous studies showed that experimental tumor growth in mice can be enhanced by low levels of circulating antibodies directed against the non-human sialic acid N-glycolyl-neuraminic acid (Neu5Gc, which accumulates in human tumors from dietary sources). However, tumor growth could instead be inhibited by anti-Neu5Gc antibodies from a different source, in a different model. Thus, anti-Neu5Gc antibodies appeared to be showing differential effects on tumor growth. However it remains generally unclear whether the immune responses that mediate cancer immunosurveillance versus those responsible for inflammatory facilitation are qualitatively and/or quantitatively distinct. Here, we address this question using multiple murine tumor growth models in which polyclonal antibodies against tumor antigens such as Neu5Gc can alter tumor progression. We found that while growth was stimulated at low antibody doses it was inhibited by high doses, over a linear and remarkably narrow range, defining an immune response curve (IRC), i.e., inverse hormesis. Moreover, modulation of immune responses against the tumor by altering antibody avidity or by enhancing innate immunity shifted the IRC in the appropriate direction. Thus, the dualistic role of immunosurveillance versus inflammation in modulating tumor progression can be quantitatively distinguished in multiple model systems, and can occur over a remarkably narrow range. We also reproduced the biphasic IRC in a model using the monoclonal anti-CD20 antibody rituximab. Furthermore, depletion of macrophages abrogated the growth promotion at low antibody concentrations and depletion of NK cells reduced growth inhibition at high antibody concentrations. These findings may have implications for the etiology and prevention of cancer, and for immunotherapeutic approaches utilizing antibodies. Citation Format: Oliver M.T. Pearce, Heinz Läubli, Andrea Verhagen, Patrick Secrest, Jiquan Zhang, Paul R. Crocker, Nissi Varki, Jack Bui, Ajit Varki. Inverse hormesis of cancer growth mediated by narrow ranges of tumor-directed antibodies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1063. doi:10.1158/1538-7445.AM2014-1063