In summary, we demonstrated feasibility to detect RB1 mutations in cfDNA of patients with advanced intraocular disease, 3/10 of whom went on to develop metastatic disease, with an ability to detect RB1 mutation in 8/10 patients by tumor‐guided genotyping, and in 6/10 patients without tumor information by de novo mutation identification. The gene discussed is RB1; the disease is neoplasm.