Shedding of tumor cell gangliosides may contribute to tumor cell escape from host immune destruction. Thus, it would be of interest to block the shedding of these immunosuppressive molecules. To this end, we studied a ceramide analogue, d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP). D-PDMP is a potent inhibitor of glucosylceramide synthase and thereby the synthesis of cellular glycosphingolipids. Exposure of LAN-5 human neuroblastoma cells to 10 µm D-PDMP for 5 days almost completely abolished the shedding of gangliosides (from 240 to 8 pmol/10⁸ cells/h), whereas cellular ganglioside synthesis was reduced by 90%. A shorter (3-day) treatment of LAN-5 cells with 10 µm D-PDMP was already effective in inhibiting shedding (by 86%) even while the cellular ganglioside content was still high. Specificity was evidence by the only minimal effect of D-PDMP on the synthesis of sphingomyelin and phosphatidylcholine. Therefore, certain pharmacological agents, such as D-PDMP, may be useful in abrogating tumor ganglioside shedding and its consequent biological effects in vivo.