Poor dietary intake is commonly associated with malnutrition in the dialysis population and oral nutritional supplementation is strategized to redress dietary inadequacy. Knowledge on clinical efficacy of whey protein supplementation (WPS) as an option to treat malnutrition in continuous ambulatory peritoneal dialysis (CAPD) patients is limited. This multicenter, parallel, open-label, randomized controlled trial investigated the clinical efficacy of WPS in 126 malnourished CAPD patients with serum albumin 0.05). A higher DPI paralleled significant increases in serum urea (mean Δ: IG = +2.39 ± 4.36 mmol/L, p = 0.002, d = 0.57 vs CG = -0.39 ± 4.59 mmol/L, p > 0.05, d = 0.07) and normalized protein catabolic rate, nPCR (mean Δ: IG = +0.11 ± 0.14 g/kg/day, p < 0.001, d = 0.63 vs CG = +0.001 ± 0.17 g/kg/day, p > 0.05, d = 0.09) for IG compared to CG patients. Although not significant, comparison for changes in post-dialysis weight (mean Δ: +0.64 ± 1.16 kg vs +0.02 ± 1.36 kg, p = 0.076, d = 0.58) and mid-arm circumference (mean Δ: +0.29 ± 0.93 cm vs -0.12 ± 0.71 cm, p = 0.079, d = 0.24) indicated trends favoring IG vs CG. Other parameters remained unaffected by treatment comparisons. CG patients had a significant decline in QOL physical component (mean Δ = -6.62 ± 16.63, p = 0.020, d = 0.47). Using changes in nPCR level as a marker of WPS intake within IG, 'positive responders' achieved significant improvement in weight, BMI, skinfold measures and serum urea (all p < 0.05), while such changes within 'negative responders' were non-significant (all p > 0.05). A single macronutrient approach with WPS in malnourished CAPD patients was shown to achieve DPI adequacy and improvements in weight, BMI, skin fold measures, serum urea and nPCR level. CLINICAL TRIAL REGISTRY: www.clinicaltrials.gov (NCT03367000).