Background: The SARS-COV 2 pandemic has hit on our lives since early 2020. During different contagion waves, both malnutrition and overweight significantly correlated with patient mortality. Immune-nutrition (IN) has shown promising results in the clinical course of pediatric inflammatory bowel disease (IBD) and in both the rate of extubation and mortality of patients admitted to an intensive care unit (ICU). Thus, we wanted to assess the effects of IN on a clinical course of patients admitted to a semi-intensive COVID-19 Unit during the fourth wave of contagion that occurred at the end of 2021. Methods: we prospectively enrolled patients admitted to the semi-intensive COVID-19 Unit of San Benedetto General hospital. All patients had a biochemical, anthropometric, high-resolution tomography chest scan (HRCT) and complete nutritional assessments at the time of admission, after oral administration of immune-nutrition (IN) formula, and at 15 days interval follow-up. Results: we enrolled 34 consecutive patients (age 70.3 ± 5.4 years, 6 F, BMI 27.0 ± 0.5 kg/m2). Main comorbidities were diabetes (20%, type 2 90 %), hyperuricemia (15%), hypertension (38%), chronic ischemic heart disease (8 %), COPD (8%), anxiety syndrome (5%), and depression (5%). 58% of patients were affected as moderately-to-severely overweight; mini nutritional assessment (MNA) score (4.8 ± 0.7) and phase angle (PA) values (3.8 ± 0.5) suggestive of malnutrition were present in 15% of patients, mainly with a history of cancer. After 15 days upon admission, we recorded 3 deaths (mean age 75.7 ± 5.1 years, BMI 26.3 ± 0.7 kg/m2) and 4 patients were admitted to the ICU. Following IN formula administration, inflammatory markers significantly decreased (p < 0.05) while BMI and PA did not worsen. These latter findings were not observed in a historical control group that did not receive IN. Only one patient needed protein-rich formula administration. Conclusions: in this overweight COVID-19 population immune-nutrition prevented malnutrition development with a significant decrease of inflammatory markers.