Background: Aside from traditional favorable localized-nodal CUP (LNC) subsets including solitary nodal disease, women with isolated axillary adenocarcinoma and squamous cell carcinoma of cervical/inguinal lymph nodes, there is limited data on disseminated nodal CUP (DNC) presentation. Our study describes the clinicopathologic features and outcomes in nodal CUP (NCUP) highlighting the DNC subset. Methods: We performed a retrospective review of 61 NCUP patients (pts) at UTMDACC (2008 - 2015). For control group (CG), we utilized a cohort of consecutive non-NCUP pts (N = 201) from MDACC CUP database (2012 - 2013). Kaplan-Meier method was used to estimate median overall survival (mOS) and compared with log-rank tests. Results: Median age of NCUP was 61 y, similar to CG (59 y; P = 0.26). In this cohort, 19/61 (31%) and 42 (69%) were classified as LNC and DNC. DNC pts were predominantly women (65%), had good performance status (0/1: 90%), and presented with intrabdominal lymphadenopathy (79%). Sixty percent had carcinoma and majority were high grade (74%). Median immunohistochemical stains performed were 9; most common positive stains were CK7 and pan-keratin. The mOS for entire NCUP cohort was 76 months (m). The mOS for LNC was not reached and was 33.1 m for DNC (HR 0.36; P = 0.04). The mOS of DNC was better than CG (18.8 m; HR 0.62; P = 0.03). Male sex and high neutrophil-lymphocyte ratio (NLR > 5) were poor prognostic factors in DNC (P< 0.01). Among NCUP pts, 21 reported subsequent development of extra-lymphatic disease [peritoneum/retroperitoneum (29%), liver (24%), lung (19%), muscle/soft tissue (19%), bone (10%)]. Among 36 pts, who had first-line systemic therapy, combination platinum-taxane was used substantially (44%) and was associated with better mOS compared to other regimens (HR 0.20; P < 0.01). Conclusions: Disseminated–lymphadenopathy CUP presentation is a unique clinical subset of CUP which is associated with a significantly better survival than non-NCUP. This distinct entity warrants dedicated research efforts towards understanding biology, developing a cost effective integrated clinical algorithm for management and developing novel therapies.