BackgroundDeep learning has been extensively used in digital histopathology. The purpose of this study was to test deep learning (DL) algorithms for predicting the vital status of whole-slide image (WSI) of uveal melanoma (UM).MethodsWe developed a deep learning model (Google-net) to predict the vital status of UM patients from histopathological images in TCGA-UVM cohort and validated it in an internal cohort. The histopathological DL features extracted from the model and then were applied to classify UM patients into two subtypes. The differences between two subtypes in clinical outcomes, tumor mutation, and microenvironment, and probability of drug therapeutic response were investigated further.ResultsWe observed that the developed DL model can achieve a high accuracy of >  = 90% for patches and WSIs prediction. Using 14 histopathological DL features, we successfully classified UM patients into Cluster1 and Cluster2 subtypes. Compared to Cluster2, patients in the Cluster1 subtype have a poor survival outcome, increased expression levels of immune-checkpoint genes, higher immune-infiltration of CD8 + T cell and CD4 + T cells, and more sensitivity to anti-PD-1 therapy. Besides, we established and verified prognostic histopathological DL-signature and gene-signature which outperformed the traditional clinical features. Finally, a well-performed nomogram combining the DL-signature and gene-signature was constructed to predict the mortality of UM patients.ConclusionsOur findings suggest that DL model can accurately predict vital status in UM patents just using histopathological images. We found out two subgroups based on histopathological DL features, which may in favor of immunotherapy and chemotherapy. Finally, a well-performing nomogram that combines DL-signature and gene-signature was constructed to give a more straightforward and reliable prognosis for UM patients in treatment and management.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12575-023-00207-0.