Methotrexate (MTX) has been widely used with a wide range of doses in the treatment of certain neoplastic diseases, severe psoriasis, and rheumatoid arthritis. At higher dose, monitoring of serum MTX elimination is performed because delayed elimination can result in serious and potentially life-threatening toxicities. A number of medications, including nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, phenylbutazone, phenytoin, sulfonamides, and some oral antibiotics, are known to interact with MTX therapy through various mechanisms. Accumulating evidence suggests that concomitant use of MTX (primarily at high doses) and proton pump inhibitors (PPIs) such as omeprazole, esomeprazole, and pantoprazole may decrease MTX clearance. The majority of the reported cases occurred with the administration of high-dose MTX in patients receiving doses of 300 mg/m2 to 12 g/m2. However, there were also cases of patients taking PPI and experiencing toxicity at doses as low as 10 mg of MTX per week. Although the dosage of MTX is small, the presence of side effect may be delayed and still dangerous. After literature review, it was found that common toxicities associated with low-dose MTX used for inflammatory arthritis include gastrointestinal adverse effects (>10%; ie nausea, stomatitis) and central nervous system toxicity (~20%; ie fatigue, malaise, dizziness, impaired cognition) with weekly administration. Bone marrow suppression (<3%; ie leukopenia, neutropenia, thrombocytopenia) and hepatotoxicity (~15%; ie reversible elevations in transaminases) are less common, and rarely MTX can also cause pulmonary (<1%) and other toxicities. Here, we report two cases who presented with severe pancytopenia 8 and 13 days after taking low-dose MTX and PPI. We highlight that in absence of risk/benefit ratio correctly set, an assessment of appropriateness of PPI prescription before MTX therapy can limit an iatrogenic risk.