Hospital malnutrition is very common and worsens the clinical course of patients while increasing costs. Lacking clinical-economic studies on the implementation of nutrition screening encouraged the evaluation of the CIPA (Control of Food Intake, Protein, Anthropometry) tool. An open, non-randomized, controlled clinical trial was conducted on patients admitted to internal medicine and general and digestive surgery wards, who were either assigned to a control (standard hospital clinical care) or to an intervention, CIPA-performing ward (412 and 411, respectively; = 823). Length of stay, mortality, readmission, in-hospital complications, and quality of life were evaluated. Cost-effectiveness was analysed in terms of cost per quality-adjusted life years (QALYs). The mean length of stay was higher in the CIPA group, though not significantly (+ 0.95 days; = 0.230). On the surgical ward, more patients from the control group moved to critical care units ( = 0.014); the other clinical variables did not vary. Quality of life at discharge was similar ( = 0.53), although slightly higher in the CIPA group at 3 months ( = 0.089). Patients under CIPA screening had a higher mean cost of € 691.6 and a mean QALY gain over a 3-month period of 0.0042. While the cost per QALY for the internal medicine patients was € 642 282, the results for surgical patients suggest that the screening tool is both less costly and more effective. The CIPA nutrition screening tool is likely to be cost-effective in surgical but not in internal medicine patients.