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Background and objectives Fat-based energy-dense nutritional supplements may offer benefits over protein- or carbohydrate-dense supplements for patients receiving dialysis because of the adverse metabolic consequences of the latter. We conducted a randomized controlled trial to assess the effects of the short-term use of a fat-based nutritional supplement on various measures of nutritional status in patients receiving maintenance hemodialysis who have low dietary energy intake. Design, setting, participants, & measurements We enrolled nondiabetic patients receiving hemodialysis for >3 months who had inadequate dietary energy intake ( Results The average age of the total population was 47 (SD: 12) years, and 55% were men. The median of dialysis vintage was 43.4 (22.5–76.3) months; 240 participants were randomly assigned to the intervention (n=120) or control group (n=120). In total, 228 (95%) participants completed the trial. The change in phase angle did not differ significantly between the intervention and control groups (estimate, 0.0; 95% confidence interval, −0.1 to 0.1 versus estimate, 0.0; 95% confidence interval, −0.1 to 0.1; estimated difference, 0.0; 95% confidence interval −0.2 to 0.2; P=0.99). None of the 19 domains of quality of life differed between the groups. Adverse events were reported in 23 (19%) participants in the control group and 40 (33%) participants in the intervention group. Conclusions In nondiabetic patients on maintenance hemodialysis, short-term administration of fat-based energy-dense nutritional supplement has no clinically significant effect on nutritional status as measured by phase angle. Podcast This article contains a podcast at https://https://www.asn-online.org/media/podcast/CJASN/2021_08_03_CJN16821020.mp3