Background: Sarcomatoid carcinoma is a rare histologic subtype of cancer of unknown primary (SCUP) characterized by poorly differentiated carcinoma with a component of sarcoma-like differentiation or a true mixed lineage neoplasm. There is limited data regarding the presentation, diagnostic algorithm and natural history of patients (pts) with SCUP. Methods: We retrospectively reviewed the MD Anderson CUP database and tumor registry from 2012-2015 and identified 26 pts with SCUP. Data regarding pathologic nomenclature, immunohistochemistry (IHC), molecular diagnostics, treatments, and outcomes were obtained. Kaplan Meier method was used for survival analyses (OS). Results: The most common nomenclature was sarcomatoid carcinoma, followed by sarcomatoid malignant neoplasm, and carcinoma with sarcomatoid features. Median age at diagnosis was 61 years (range 33-77). 54% of pts were female. Majority of pts presented with more than 3 metastatic sites, commonly lung, liver, and bone. 22 pts (85%) received chemotherapy, most commonly gemcitabine + docetaxel (10 [38%]) and carboplatin + paclitaxel (4 [15%]). Epithelial IHC markers included Pankeratin (AE1/AE3), CK7, BerEp4, Low Molecular Weight keratin and mesenchymal IHC markers included Calretinin, SMA, Vimentin, Mesothelin. Median OS for entire cohort was 7 months (m) (95% CI: 2.1-11.9). Pts who underwent definitive multimodality management did significantly better compared to pts with palliative therapy alone (median OS 26 vs 7 m: HR 0.25; 95% CI: 0.11-0.58, P = 0.003). Poor PS (HR 3.49; 95% CI 1.28-9.53, P = 0.0005), elevated LDH (HR 2.81; 95% CI 0.68-11.63; P = 0.03), and elevated neutrophil-to-lymphocyte ratio (NLR) (HR 3.18; 95% CI: 1.07-9.48, P = 0.002) were associated with poor OS. 5 pts underwent NGS which demonstrated p53 (3), BRAF V600E (2) and EGFR amplification (1). Conclusions: SCUP is a rare presentation with an aggressive course and limited survival. The diagnosis is difficult to make and requires a careful review and synthesis of histology, IHC, and molecular diagnostics. Further research is needed to better understand the optimal use of molecular diagnostics in order to more optimally diagnose and treat this disease.