Key PointsQuestionIs oral S-1 chemotherapy with simultaneous integrated boost radiotherapy (SIB-RT) effective and safe for patients aged 70 years and older with inoperable esophageal cancer (EC)?FindingsIn this randomized clinical trial of 330 patients aged 70 years and older with EC who were randomly assigned to receive SIB-RT with concurrent and consolidated oral S-1 chemotherapy (CRTCT) or SIB-RT alone, 3-year overall survival and progression-free survival of participants in the CRTCT group were superior to that of SIB-RT group. The incidence of grade 3 to 5 toxic effects was similar in both groups.MeaningThese findings suggest that oral S-1 chemotherapy with SIB-RT should be considered as an alternative treatment option for patients aged 70 years and older with inoperable EC to improve survival outcomes with acceptable treatment-related toxic effects.