The matrix metalloproteinases (MMPs) are implicated in connective tissue destruction during cancer invasion and metastasis. A naturally occurring variant arising from the insertion or deletion of a guanine in the promoter of the MMP-1 gene has recently been reported and shown to influence its transcriptional activity in melanoma cells. In this study, MMP-1 genotype was determined in 139 Caucasian patients with cutaneous malignant melanoma. The insertion allele was associated with deep invasive, and therefore poorer-prognosis, primary tumors [(34% of patients with vertical growth phase tumor were homozygous for the insertion allele compared with 17% of patients with horizontal growth phase tumor (P = 0.0333; odds ratio = 2.51)]. These data suggest that the invasiveness of cutaneous malignant melanoma is influenced by variation in the MMP-1 gene promoter that affects MMP-1 expression.