Carcinoma of unknown primary (CUP) is a difficult-to-manage malignancy. Multi-omic profiles and treatment outcome versus degree of precision matching was assessed. Tumors underwent next-generation sequencing (NGS) [tissue and/or blood-derived cell-free DNA (cfDNA)]. Selected patients had transcriptome-based immune profiling and/or programmed cell death 1 ligand 1 (PD-L1) immunohistochemistry analysis. Patients could be reviewed by a Molecular Tumor Board, but physicians chose the therapy. Of 6,497 patients in the precision database, 97 had CUP. The median number of pathogenic tissue genomic alterations was 4 (range 0-25) and, for cfDNA, was 2 (range 0-9). Each patient had a distinct molecular landscape. Food and Drug Administration (FDA)-approved biomarkers included: PD-L1+ ≥1%, 30.9% of CUPs tested; microsatellite instability, 3.6%; tumor mutational burden ≥10 mutations/mb, 23%; neurotrophic receptor tyrosine kinase (NTRK) fusions, 0%. RNA-based immunograms showed theoretically druggable targets: lymphocyte activationgene 3 protein (LAG-3), macrophage colony-stimulating factor 1 receptor (CSF1R), adenosine receptor A2 (ADORA2) and indoleamine2,3-dioxygenase 1 (IDO1). Overall, 56% of patients had ≥1 actionable biomarker (OncoKB database). To quantify the degree of matching (tumors to drugs), a matching score (MS) (roughly equivalent to number of alterations targeted/ total number of deleterious alterations) was calculated post hoc. Comparing evaluable treated patients [MS high, >50% (N=15) versus low ≤50% (N=47)], median progression-free survival was 10.4 vs. 2.8 months (95% CI 0.11-0.64; HR 0.27; P=0.002); survival, 15.8 vs. 6.9 months (95% CI 0.17-1.16; HR 0.45; P=0.09); and clinical benefit rate (stable disease ≥6 months/partial/complete response), 71% vs. 24% (P=0.003). Higher MS was the only factor that predicted improvement in outcome variables after multivariate analysis. In conclusion, CUPs are molecularly complex. Treatments with high degrees of matching to molecular alterations (generally achieved by individualized combinations) correlated with improved outcomes.