The aim of this study was to verify the clinical efficacy of a diet associated with already commercially available oral amino acid functional cluster (AFC) compared to the administration of a diet associated with a nitrogen protein-based supplement (casein) in antagonizing malnutrition in patients with Chronic renal failure (CRF) undergoing haemodialysis. The secondary aim was to assess the changes in protein levels during the acute phase such as the expression of inflammatory cytokines. Twenty patients in haemodialysis aged between 18 and 85 of both genders (13 m, 7f) were recruited, randomized and divided into two groups and treated for 4 months respectively with: (1) oral AFC supplement (*)8 g/die: group A, and (2) oral supplementation of a protein nitrogenous mixture compared to AFC with a casein protein source) of 6.6 g: group P. During the initial assessment and thereafter on a monthly basis all patients underwent the following: Dietary recall 24 h; Anthropometric: Weight, height, BMI, expected dry weight, actual weight; Biochemical: Albumin, transferrin, Na, K, Cl, Ca, P, Mg, long-interval creatinine (Aminotrofic(®): Errekappa Euroterapici, Milano) pre-albumin, α1 acid glycoprotein, C reactive protein (CRP), protein nitrogen appearance (PNA); Instrumental: Handgrip strength evaluation, Calorimetry by means of Armband, Bio-impedance analysis (BIA), Spitzer Index (quality of life), Subjective Global Assessment Generated by the patient (PG SGA). Considering the nutritional parameters, no significant differences concerning dry weight emerged between the beginning (T0) and the end (T4) (weight A to T0: kg 64.41 ± 6.34; weight A to T4: kg 64.51 ± 7.05: P = NS; weight P to T0: kg 60.17 ± 11.94; weight P to T4: kg 59.86 ± 11.43: P = NS); biochemical parameters, significant differences were observed only for two parameters: pre-albumin (Pre-albumin A to T0 30.12 ± 7.23; Pre-albumin A to T4: 28.91 ± 5.8; Pre-albumin P to T0 22.51 ± 6.04; Pre-albumin P to T4: 26.10 ± 9.82), and Transferrin (Transferrin A to T0 171.77 ± 28.87 mg/dL, Transferrin A to T4: 181.44 ± 38.83 mg/dL: P < 0.005; Transferrin P to T0 160.29 ± 27.46 mg/dL, Transferrin P to T4: 146.57 ± 24.96 mg/dL: P < 0.005), but not in other parameters. From a nutritional perspective, after 4 months of treatment an increase in protein synthesis was noted in group A compared to group P which was proved by the significant increase of transferrin. This pilot study suggests the AFC oral supplementation may represent a valid alternative to intradialytic parenteral treatment and may also allow for an improvement in blood chemical values and nutritional status.