The G-308A polymorphism of the tumour necrosis factor-alpha (TNF-alpha) gene, a variant that influences TNF-alpha transcription, may contribute to non-ischaemic dilated cardiomyopathy. To evaluate whether TNF-alpha genotyping may assist in identifying a subset of patients who could potentially benefit from immunomodulatory therapy, we assessed the relationship between the G-308A polymorphism of the TNF-alpha gene and changes in left ventricular (LV ) chamber dimensions and systolic function in patients with idiopathic dilated cardiomyopathy (IDC) before and six months after diuretic, digoxin and angiotensin-converting enzyme inhibitor (ACEI) therapy. In 331 patients with IDC and 349 controls, the TNF-2 (A) allele (odds ratio = 1.509, 95% CI = 1.130-2.015, p < 0.01) and the TNF-12/22 (AG/GG) genotype (odds ratio = 1.620, 95% CI = 1.159-2.266, p < 0.01) were associated with IDC. However, in 122 patients with IDC, the TNF-alpha genotype was not associated with plasma TNF-alpha concentrations. In 133 patients with IDC, the TNF-alpha genotype failed to predict either the severity of pump dysfunction and cardiac dilatation at baseline, or changes in pump function and cardiac dimensions after six months of medical treatment. We conclude therefore that although the TNF-alpha gene G-308A polymorphism may contribute to the development of IDC, it does not influence pump function or adverse cardiac remodelling in patients with IDC. Genotyping for this variant is therefore unlikely to assist in identifying patients with heart failure who may be particularly susceptible to novel immunomodulatory therapeutic strategies.