Leucovorin (folinic acid) is used with methotrexate mainly as “leucovorin rescue” to reduce methotrexate toxicity in normal cells.

It is given after high-dose methotrexate, not simultaneously, so methotrexate has time to exert its anti-cancer effect before normal tissue is rescued. Timing and dose depend on methotrexate blood levels and renal function. It is also used for methotrexate overdose or delayed clearance. This bypass mechanism is described in Harrison's Principles of Internal Medicine, where leucovorin rescues cells from methotrexate’s folate blockade.

A different use occurs with low-dose methotrexate for rheumatologic disease: folic acid or leucovorin may be prescribed to reduce adverse effects such as mouth sores, nausea, and elevated liver enzymes. The schedule should be set by the prescriber because excessive or poorly timed leucovorin can reduce methotrexate effectiveness in some settings.

The FDA labeling specifically recognizes leucovorin rescue after high-dose methotrexate and for toxicity from impaired methotrexate elimination or overdose, with methotrexate levels monitored to guide treatment (FDA leucovorin label).