Background: Provision of oral protein in hemodialysis (HD) is desirable due to improved compliance to protein requirements and better nutritional status, but the risks of hypotension and underdialysis need to be considered. This study compared 2 different timings for administering oral nutritional supplements (ONS), predialysis and mid-dialysis, with respect to hemodynamics, dialysis adequacy, urea removal, and tolerability. Methods: This single-center, prospective crossover study analyzed 72 stable patients with ESRD on twice a week maintenance HD with a mean age of 38.7 (±11.2) years and a dialysis vintage of 28.2 (±13.1) months. In the first week, all the patients received ONS (450 kcal energy, 20 g protein) 1 h prior to start of dialysis (group 1) and in the next week, the supplement was administered after 2 h of start of dialysis (group 2), with a predialysis fasting period of at least 3 h in both groups. Blood pressures, serum, and spent dialysate samples were collected and nausea occurrence was noted by severity. Results: Predialytic intake (group 1) was associated with higher predialysis and 1st hour blood urea, dialysis adequacy, and urea removal than group 2. Both groups achieved mean Kt/V > 1.2, and the occurrence of symptomatic hypotensive episodes and nausea was not significantly different between the groups. On repeated measures ANOVA, changes in blood urea over time showed significant group effect. Conclusions: Predialytic supplementation was associated with better dialysis adequacy and urea removal than intradialytic supplementation. However, both timings were equally tolerated and not associated with underdialysis.