Objective To evaluate the effectiveness of a high calorie and protein, β-hydroxy-β-methylbutyrate containing oral nutritional supplement (HP-HMB-ONS), on nutritional status, activities of daily living and quality of life (QoL) in old malnourished subjects. Methods We conducted an observational, prospective, open label, multicenter study. Participants were > 65 years, undernourished or at nutritional risk Nutrition Risk Score (NRS) ≥ 3 and had been included on an ONS (HP-HMB-ONS twice daily for 12 weeks) per standard of care. Visits at baseline (V1), 6 weeks (V2) and 12 weeks (V3) were performed. The primary endpoints were gain of body weight, change in body mass index (BMI) and NRS 2002 index. Data from QoL (EQ-5D-3L) and activities of daily living (Katz index) were also collected. Results A total of 235 participants were included in the study. Of these 148 took at least a 75% of the HP-HMB-ONS and were included in the analysis (per protocol); median age was 80.0 (SD:8.3) years, 65.5% ( n  = 97) were female, 67.6% ( n  = 100) had 2 or more diseases. At V3, a statistically significant increase in weight (2.1 kg; SD: 3.8) ( p  < 0.001) and BMI (0.8 kg/m 2 ; SD: 1.45) were found compared to V1, whereas NRS 2002 values decreased by 0.9 (SD: 1.2). A significant ( p  < 0.001) improvement in Katz index (mean change = 0.3; SD:1.4) and EQ-5D scoring (mean change = 0.5; SD:1.9) compared to V1, were also reported. Conclusions The results suggest that administration of a HP-HMB-ONS improve the nutritional status and may led to a significant improvement in patients’ activities of daily living and QoL, independent of baseline BMI.