Piritrexim is a synthetic antifolate agent with antiparasitic, antipsoriatic and antitumor properties. Piritrexim inhibits the enzyme dihydrofolate reductase, thereby disrupting folate metabolism and DNA synthesis and cell division. A theoretical advantage of piritrexim over trimetrexate is a lack of any known effects on histamine metabolism, which may lower the risk of hypersensitivity reactions. Piritrexim is a nonclassical antifolate for antitumor and parasitic chemotherapy that passively diffuses into cells and hence do not have to depend on folylpoly-gamma-glutamate synthetase or the reduced folate carrier. Because piritrexim is not a substrate for polyglutamation, the drug is not selectively retained within cells for prolonged periods. Piritrexim has a reliably high oral bioavailability of about 75%, which has led to its development as an oral lipophilic antifolate. Most commonly, it has been administered in oral daily doses of 75 to 150 mg bid or tid every 5 days, with cycles repeated every 3 weeks. Oral absorption is rapid, with peak plasma levels appearing at 1.5 hours after ingestion. Elimination occurs primarily via hepatic metabolism of the drug to active metabolites, and the terminal half-life of the parent compound is about 1.5 to 4.5 hours. Single-agent oral piritrexim has clinical activity in melanoma, urothelial cancers, and head and neck cancers. Tolerable combinations of piritrexim with cisplatin, fluorouracil, and leucovorin have been tested, with promising results achieved in head and neck cancer. An interesting attempt to alternate piritrexim with methotrexate did not have any greater activity than methotrexate alone.