UNLABELLED: Chronic inflammation and metabolic dysregulation of heart failure (HF) often result in sarcopenia. The combined effect of Mediterranean diet (MD) and omega-3 polyunsaturated fatty acids on the advanced lipidomic profile of HF patients remains poorly defined. OBJECTIVE: Our objective was to analyze the specific effects of a MD plus omega-3-enriched oral nutritional supplements (MD+ONS) versus MD alone on the metabolic lipid profile of patients with HF, stratified by sarcopenia status. METHODS: In this prospective, open-label, randomized controlled trial, 38 patients with HF were assigned to MD alone or MD+ONS (24 weeks). Advanced lipoprotein profiling (triglycerides, cholesterol, particle size, and concentration for VLDL, LDL, and HDL subclasses) was performed using 2D 1H-NMR spectroscopy. RESULTS: At baseline, NT-proBNP levels correlated positively with ω6/ω7ω9 fatty acids and IDL-TG (p < 0.05). Over 24 weeks, VLDL-C, VLDL-TG, and VLDL-P significantly decreased in the whole cohort (p < 0.001). However, stratified analysis revealed that in patients with sarcopenia, these reductions were primarily driven in the MD group (p < 0.01). Conversely, in patients without sarcopenia, the MD+ONS group showed significant reductions in VLDL-TG, VLDL-P, and VLDL-Z (p < 0.05). Regarding intermediate lipoproteins, IDL-C significantly increased in the MD group (p < 0.05) but not in the MD+ONS group. In the LDL fraction, total LDL-P and small LDL-P decreased in the MD group (p < 0.05), while medium LDL-P increased across both groups (p < 0.01). Total HDL-P decreased (p < 0.05), yet large HDL-P significantly increased in the whole cohort and the MD group (p < 0.05). No significant changes were observed in structural lipids or total fatty acid families. CONCLUSIONS: MD+ONS induces lipidomic shifts that are significantly modulated by baseline sarcopenia. The intervention appears to stabilize VLDL and IDL levels in patients with sarcopenia compared to diet alone, while promoting a more favorable VLDL reduction in individuals without sarcopenia, suggesting that early nutritional support for improving body composition is a critical determinant of the metabolic response to specific interventions in patients with HF.