PURPOSE: Determination of reliable change of radiomics feature over time is essential and vital in delta-radiomics, but has not yet been rigorously examined. This study attempts to propose a methodological approach using reliable change index (RCI), a statistical metric to determine the reliability of quantitative biomarker changes by accounting for the baseline measurement standard error, in delta-radiomics. The use of RCI was demonstrated with the MRI data acquired from a group of prostate cancer (PCa) patients treated by 1.5 T MRI-guided radiotherapy (MRgRT). METHODS: Fifty consecutive PCa patients who underwent five-fractionated MRgRT were retrospectively included, and 1023 radiomics features were extracted from the clinical target volume (CTV) and planning target volume (PTV). The two MRI datasets acquired at the first fraction (MRI11 and MRI21) were used to calculate the baseline feature reliability against image acquisition using intraclass correlation coefficient (ICC). The RCI was constructed based on the baseline feature measurement standard deviation, ICC, and feature value differences at two time points between the fifth (MRI51) and the first fraction MRI (MRI11). The reliable change of features was determined in each patient only if the calculated RCI was over 1.96 or smaller than -1.96. The feature changes between MRI51 and MRI11 were correlated to two patient-reported quality-of-life clinical endpoints of urinary domain summary score (UDSS) and bowel domain summary score (BDSS) in 35 patients using the Spearman correlation test. Only the significant correlations between a feature that was reliably changed in ≥7 patients (20%) by RCI and an endpoint were considered as true significant correlations. RESULTS: The 352 (34.4%) and 386 (37.7%) features among all 1023 features were determined by RCI to be reliably changed in more than five (10%) patients in the CTV and PTV, respectively. Nineteen features were found reliably changed in the CTV and 31 features in the PTV, respectively, in 10 (20%) or more patients. These features were not necessarily associated with significantly different longitudinal feature values (group p-value < 0.05). Most reliably changed features in more than 10 patients had excellent or good baseline test-retest reliability ICC, while none showed poor reliability. The RCI method ruled out the features to be reliably changed when substantial feature measurement bias was presented. After applying the RCI criterion, only four and five true significant correlations were confirmed with UDSS and BDSS in the CTV, respectively, with low true significance correlation rates of 10.8% (4/37) and 17.9% (5/28). No true significant correlations were found in the PTV. CONCLUSIONS: The RCI method was proposed for delta-radiomics and demonstrated using PCa MRgRT data. The RCI has advantages over some other statistical metrics commonly used in the previous delta-radiomics studies, and is useful to reliably identify the longitudinal radiomics feature change on an individual basis. This proposed RCI method should be helpful for the development of essential feature selection methodology in delta-radiomics.