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The GISSI-HF trial showed that n-3 polyunsaturated fatty acids (PUFA), but not rosuvastatin, reduce morbidity and mortality in patients with symptomatic heart failure (HF) of any cause. The aim of this echocardiographic substudy of GISSI-HF was to investigate the effects of n-3 PUFA and of rosuvastatin on left ventricular (LV) function in such patients.Six hundred and eight chronic HF patients were randomized to n-3 PUFA (n = 312) or placebo (n = 296); a second randomization was performed to rosuvastatin (n = 212) or placebo (n = 207). Echocardiographic examinations were recorded at baseline and at 1, 2, and 3 years; offline analysis was performed by a core laboratory to ensure consistent quantitative analysis. Baseline LV ejection fraction (EF) was 30% (95%CI 29–31). Left ventricular ejection fraction increased with n-3 PUFA by 8.1% at 1 year, 11.1% at 2 years, and 11.5% at 3 years vs. 6.3% at 1 year, 8.2% at 2 years, and 9.9% at 3 years in the placebo group (P = 0.0050). No other echocardiographic parameter changed significantly. Rosuvastatin effects were not statistically significant.n-3 PUFA can provide a small but statistically significant advantage in terms of LV function in patients with symptomatic HF of any aetiology, already treated with recommended therapies.