Thrombocytopenia is a common adverse event of oxaliplatin-based chemotherapy. Grade 2 or higher oxaliplatin-related thrombocytopenia may result in dose reduction, discontinuation or delay initiation of chemotherapy and may adversely affect the therapeutic efficacy and even overall survival of patients. Early recognition of patients at risk of developing grade 2 or higher thrombocytopenia is critical. However, to date there is no well-established method to early identify patients at high risk. The aims of this study were to develop and validate a contrast-enhanced CT-based whole-spleen radiomics signature for early prediction of grade 2 or higher thrombocytopenia in patients with gastrointestinal malignancies treated with oxaliplatin-based chemotherapy and to explore the incremental value of combining the radiomics signature and conventional clinical factors for risk prediction.A total of 119 patients with gastrointestinal malignancies receiving oxaliplatin-based chemotherapy from March 2017 to December 2020 were retrospectively included and randomly divided into a training cohort (n = 85) and a validation cohort (n = 34). Grade 2 or higher thrombocytopenia occurred in 26.1% of patients (22 and nine patients in the training and validation cohort, respectively) with a median time interval of 101 days from the start of chemotherapy. The whole-spleen radiomics features were extracted on the portal venous phase of the first follow-up CT images. The least absolute shrinkage and selection operator (LASSO) algorithm was applied to select radiomics features and to build the radiomics signature for the prediction of grade 2 or higher thrombocytopenia. A clinical model that included clinical factors only and a clinical-radiomics model that incorporated clinical factors and radiomics signature were constructed. The performances of both models were evaluated and compared in the training, validation and the whole cohorts.The radiomics signature yielded favorable performance in predicting grade 2 or higher thrombocytopenia, with the area under the curve (AUC), sensitivity and specificity being 0.865, 81.8% and 84.1% in the training cohort and 0.747, 77.8% and 80.0% in the validation cohort. The AUCs of the clinical-radiomics model in the training and validation cohorts reached 0.913 (95% CI [0.720-0.935]) and 0.867 (95% CI [0.727-1.000]), greater than the AUCs of the clinical model. Integrated discrimination improvement (IDI) index showed that incorporating radiomic signature into conventional clinical factors significantly improved the predictive accuracy by 17.0% (95% CI [4.9%-29.1%], p = 0.006) in the whole cohort.Contrast-enhanced CT-based whole-spleen radiomics signature might serve as an early predictor for grade 2 or higher thrombocytopenia during oxaliplatin-based chemotherapy in patients with gastrointestinal malignancies and provide incremental value over conventional clinical factors.©2023 Dai et al.