Leptomeningeal carcinomatosis occurs occasionally in patients with solid malignancies and carries a poor prognosis despite treatment with systemic chemotherapy and/or radiotherapy. We describe the case of a 43 year old man who presented with leptomeningeal carcinomatosis secondary to malignant melanoma. The patient received intraventricular delivery of NIH3T3 producer cells expressing the thymidine kinase (HSV-Tk1) gene via a retroviral vector followed by intravenous ganciclovir. He experienced abrupt and severe meningeal irritation and hyperpyrexia immediately after injection of the producer cells into the ventricular CSF. Vector producer cells (VPC) survived and were detected by NeoR marker gene expression in the CSF for a week, until a single dose of ganciclovir (GCV) was followed by a decline in the copy number of the NeoR marker gene to undetectable levels over 24 h. This decline upon introduction of ganciclovir suggests effective distribution of ganciclovir to producer cells bearing the HSV-Tk gene. The patient survived 9 months after treatment. Side-effects from the treatment included acute hyperpyrexia which was short-lived and medically manageable.