There have been no studies as yet that have evaluated how hemodialysis (HD) schedules affect the day of the week of hospitalization for cardiovascular diseases (CVDs) and infectious diseases (IDs), over a period of time. Herein, we performed a retrospective observational cohort study (1995 -2014) evaluating 11,111 hospitalizations in 1,953 patients with end-stage renal disease, receiving HD 3 times a week (following either a Monday-Wednesday-Friday [MWF] schedule or a Tuesday-Thursday-Saturday [TTS] schedule) or receiving frequent HD (FHD) at least 4 times a week. Overall, hospitalization rates for CVDs and IDs were the highest on Monday in the MWF schedule and Tuesday in the TTS schedule compared to the average rates for all the days of the week. When generalized estimating equations (GEEs) were used in conjunction with robust variance estimators of each type of CVD, the risk for pulmonary edema was found to be significantly higher on Sunday and Monday in the MWF schedule and Monday and Tuesday in the TTS schedule. For both cerebrovascular and ischemic heart disease, the risks were significantly higher on Tuesday in the MWF schedule and Wednesday in the TTS schedule. Moreover, there were significant differences in the day of the week risks among the various CVD types. On trend analysis, the overall hospitalization rate for CVDs on the first HD day did not decrease (P = 0.2); however, the hospitalization rate for IDs on the first HD day significantly decreased (P = 0.02) over a span of 20 years. When GEEs were used in the case of FHD patients with severe heart failure, the hospitalization rate on the first HD day (Monday) significantly decreased after FHD initiation (P = 0.04). It was found that HD schedules affected the day of the week of hospitalization for CVDs. FHD may lower the day of the week risk.