Methotrexate (MTX) was originally synthesised as an anti-cancer drug. Soon it was also used in immunoinflammatory diseases, mainly in the field of rheumatology. However, the dose used in oncology is several-fold higher as compared to the dose used in systemic immunoinflammatory rheumatological diseases. This led to the use of terms 'low-dose MTX' (LD-MTX) and 'high-dose MTX' (HD-MTX) respectively for its use in immunoinflammatory rheumatological diseases as against its use in oncology. Extensive studies have demonstrated that therapeutic action, clinical indications, adverse effects and mechanisms of action of LD-MTX and HD-MTX are quite different. It is somewhat akin to low-dose aspirin versus high-dose aspirin with entirely different spectra of therapeutic action and adverse effects. It is important to understand this difference. This would help in allaying unfounded fear of adverse effects of LD-MTX that is often mistakenly considered the same as that of HD-MTX used in oncology.