Malignant uveal melanoma is the commonest primary intraocular tumour in adults. It metastasizes frequently and 50% of patients die within 10 years of diagnosis. The expression of cyclin D1, p53, and MDM2 in uveal melanoma and their relationship to metastasis-free 5-year survival was determined, in order to investigate whether these proteins help to distinguish those patients with a favourable prognosis from those with a poorer one. Ninety-six eyes enucleated for uveal melanomas were immunohistochemically analysed for the protein expression of cyclin D1 and related cell-cycle markers, p53 and MDM2. The evaluation of the specimens was undertaken by two independent pathologists without knowledge of the outcome. Statistical analysis of clinical, morphological, and immunohistological features was performed. A favourable outcome' was deยฎned as survival of at least 5 years after diagnosis, without metastases (n=57). An unfavourable outcome' was deยฎned as death from metastases within the ยฎrst 5 years after diagnosis of uveal melanoma (n=39). Cyclin D1 positivity (>15% positive tumour cells) as well as p53 positivity (>15% positive tumour cells) was associated with an unfavourable outcome (for cyclin D1: odds ratio=4.2, 95% conยฎdence interval 1.5ยฑ11.8, p=0.006; for p53: odds ratio=3.2, 95% conยฎdence interval 1.1ยฑ9.3, p=0.03). In addition, cyclin D1 positivity was associated with the presence of extraocular extension of the tumour ( p=0.01), with the mixed or epithelioid cell type ( p=0.02), and with the tumour cell MIB-1 positivity ( p=0.0001). MDM2 immunoreactivity of the tumour cells showed a potential correlation with clinical outcome (odds ratio=2.1, 95% conยฎdence interval 0.8ยฑ5.8, p=0.13). Multiple logistic regression models showed that cyclin D1 positivity is an independent prognostic factor after control for other prognostic markers. The expression of cyclin D1 in uveal melanoma is associated with a more aggressive course and histologically unfavourable disease. This could serve as a further independent prognostic factor in uveal melanoma.