Background: There is a lack of active treatment against mUM. Such “hard-to-treat” tumour might benefit from treatment decisions driven by a complete genomic and transcriptomic analysis program. Methods: From 1.3.2016 to 1.12.2017, mUM were included in the prospective TREAT20Plus study and were subjected to a CMTA including WGS, WES, RNAseq, cell culture and systems biological/pharmacodynamic modelling. Treatment recommendations were made by a molecular tumour board. Results: Twenty six patients (12 F, 14M). Age: 61 (32-80). PS: 0 (0-2). Metastases: 4 (1-10). Abnormal LDH: 19. Pre-treatment: 1 (0-5) and type: iv chemotherapy: 11, checkpoint-inhibitors (-i): 7, intra-hepatic: 13, vaccine: 1. Insufficient material in 3 patients. The mutation burden was low: 32 (15-449). The treatment recommendations (TRec) were based on the different mutations or activation profiles: A) MEK-i. for mutations of GNAQ: 11, GNA11: 13. B) a MET-i. for MET overexpression: 17. ALK-i. for the oncogenic ALK^ATI isoform: 3. C) CDK4/6-i. for CDKN2A loss: 1. D) checkpoint-i. for mutation burden > 100: 3. E) For the other alterations no off-label treatment was available: mutation of BAP1: 8 or SF3B1: 10, overexpression of MYC: 14, BCL2: 24, CCND2: 16, ERBB3: 5 , biallelic loss of TNFAIP3: 1. Among novel non-recurring gene-fusions: inactivating gene fusion affecting MITF: 1. In 1 patient repeated biopsies at time of recurrence after MEK-i disclosed biallelic loss of CDKN2A. The pharmacodynamic modeling confirmed TREc in 10 and helped with the decision in 8 patients. A treatment was initiated in 15 patients: Trametinib: 6, Cabozantinib: 3, Crizotinib: 6, Palbociclib: 1. A treatment was not initiated for 8 patients: 4 too early, 4 rapid progression. Among the 12 evaluable patients the antitumor response was: minor response: 2, stable disease: 4, progressive disease: 5, too early: 1. Median PFS of the treated patients: 5,5 months. Conclusions: Precision medicine in mUM is clinically feasible. It leads to a better understanding of the biology of the tumour and of the potential therapeutic targets. Its clinical efficacy is limited by the non-availability of drugs as single agent or in combination. Clinical trial information: EA4/063/13.