Leptomeningeal metastases occur in 0.8-8% of cancer patients. Despite recent developments in cancer therapy, survival of these patients is usually less than six months. Here, we describe an easy and reproducible mouse model of leptomeningeal metastases through intracisternal injection of B16F-10 murine melanoma cells, with histological characteristics comparable with human leptomeningeal metastases. After intracisternal injection of a recombinant adenoviral vector containing the LacZ gene, we found transfected cells in ependymal and subependymal cells throughout the brain, but not in parenchymal cells. Intracisternal injection of adenoviral vector, preceded by daily intracisternal injections with saline, did not result in a decreased vector delivery. After a single intracisternal injection, gene expression persisted for at least a month in immunodeficient mice, without apparent toxicity or decrease in intensity. The results of this study show the facility of a mouse model for leptomeningeal metastases as well as repeated intrathecal drug delivery.