BACKGROUND: Metabolic syndrome (MetS) patients have impaired hypothalamic regulatory functions involved in food intake and energy expenditure and suffer from a state of meta-inflammation. Pre-clinical studies demonstrated that ultramicronized palmitoylethanolamide (PEA) acts both on the adipose tissue and the central nervous system, while hydroxytyrosol (HTyr) counteracts several types of dysmetabolism. OBJECTIVES: The aim of our randomized crossover double-blind placebo-controlled pilot study was to evaluate the potential effects of a food supplement (FS) containing a co-micronized formulation of PEA and rutin along with HTyr, combined with a tailored calorie-controlled Mediterranean diet, in patients with MetS. METHODS: Nineteen patients were enrolled and block-randomized to an eight-week MD together with the FS or placebo. After a two-week washout period, the treatments were reversed. Data on laboratory parameters and those detected by capillary sampling, anthropometry, body composition analysis, ultrasound examination, blood pressure monitoring, the 36-Item Short-Form Health Survey questionnaire, handgrip strength test, and physical performance tests were collected at each time point (protocol code R.S. 262.22, registered on 20 December 2022). RESULTS: At the end of the study, patients supplemented with the FS showed a significant reduction in body weight, body mass index, fat mass, and inflammation biomarkers (CRP and ESR), compared to placebo-supplemented patients. In contrast, the fat-free mass, phase angle, and body cell mass were increased in FS compared to placebo patients. CONCLUSIONS: Although preliminary, the results of our clinical study suggest that co-micronized PEA-rutin and HTyr may be of help against adiposopathy in patients with MetS.