Abstract Purpose: The metastasis of ovarian cancer to the omentum is associated with poor clinical outcomes. Although the omentum has immune function due to the activities of milky spots, the role of the omentum in anti-tumor immunity has not been rigorously addressed. We hypothesize that the omentum directly modulates anti-tumor immunity to metastasized tumor cells. Experimental procedure: We examined metastases and immunological function in mice that expresses SV40 T antigen oncogene under the Mullerian Inhibitory Substance type II Receptor promoter (MISIIR-Tag). In separate experiments we also implanted 3 x 106 EG7.1.15 cells (murine thymoma that express chicken ovalbumin (OVA)) intraperitoneally (i.p.) to induce peritoneal tumors. We used flow cytometry to analyze cells from the omentum and peritoneal exudate from mice with or without tumors. Results: Omental tumor growth induced by EG7.1.15 cells is associated with an increase in CD4+CD25+FoxP3+ T regulatory cells (Tregs) and CD103+ DCs, while tumor-specific CD8+ T cells are reduced. Although tumor-specific CD8+ T cells generated in the periphery prior to tumor onset prevent omental and peritoneal tumor growth, tumor-specific CD8+ T cells generated after tumors are established in the omentum are unable to mediate tumor clearance. The induction of tolerance requires the omentum, is dependent on FoxP3+ Tregs, is tumor antigen-specific and takes place in as few as 6 days. The metastasis of ovarian tumor cells into the omentum also correlates with an increase in Tregs. Deleting Tregs in both models reduces tumor burden. Conclusions: Metastasis of tumor cells to the omentum leads to immunological tolerance rather than immunity – even when tumor cells express foreign antigens. Thus, the omentum has an immunological activity that prevents, rather than promotes, immunity to peritoneal tumors. Citation Format: Selene Meza-Perez, Maria de la Luz Garcia-Hernandez, Aaron Silva-Sanchez, Javier Rangel-Moreno, Uma Mudunuru, Edith M Lord PhD, Troy D. Randall. Omentum promotes suppression against peritoneal tumors [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1337.