Background: Isolated or predominant carcinomatosis is not an uncommon presentation in patients with carcinoma of unknown primary (CUP). Primary peritoneal serous carcinoma (PPSC) is a well studied favorable CUP subset though data on non–PPSC is lacking and this group comprises of a large differential (gastric, colorectal, appendiceal, pancreatico-biliary and other cancer profiles). Information on the clinicopathologic characteristics and survival of these patients can help articulate a management strategy for these patients. Methods: Review of a M. D. Anderson Cancer Center CUP database from 2005 to 2010 has identified 64 patients in an ongoing study. Patients with predominant disease sites other than peritoneum/omentum were excluded. Data on demographics, imaging, detailed pathology, treatment, clinical course and survival was collected. Results: Median age of the patients is 56 years (range 31-86) and 38% are male. 13 (20%) women presented with typical PPSC. Immunohistochemistry (IHC) for all patients included a large range of markers – the most helpful in diagnosis were CK 7 (positive 46/72%), CK 20 (positive 33/51%), CDX-2 (positive 28, 44%), WT-1 (positive 9, 14%) and Calretinin (positive 2, 3%). 43 (67%) patients presented with ascites. First line treatments were grouped into: Colorectal regimens (FOLFOX/FOLFIRI based -30 pts/47%); Pancreaticobiliary regimens (Gemcitabine based - 5 pts/ 8%), taxane+platinum -21 pts/33%); other or no therapy -8 pts/12%. Median overall survival was 25 months (CI 20-30 months; OS not reached for PPSC and 22 months for non-PPSC patients). Conclusions: Uniform and limited IHC including CK 7/20; CDX-2, WT-1 and Calretinin are the most helpful first tier IHC in determining the cancer profile and choosing the best treatment strategy for isolated carcinomatosis CUP patients. Non-PPSC carcinomatosis is not an uncommon CUP presentation and these patients often are candidates for non taxane based therapies. Patients with a GI cancer (CDX-2 positive non-PPSC) IHC profile are good candidates for the colorectal armanentarium of drugs with survival of these patients similar to patients with metastatic colorectal cancer.