Background Skin toxicity during low-dose methotrexate therapy is rare, ill described, and reported to have nonspecific histologic characteristics. Thus, misdiagnosis is common in patients with mucosal ulcers and/or skin erosions related to low-dose methotrexate. Objective We sought to describe the features of skin toxicity induced by low-dose methotrexate. Methods We evaluated the clinical and histologic features in 5 patients who experienced skin toxicity induced by low-dose methotrexate between 2011 and 2013. Results All 5 patients had acute mucosal ulcers, 4 had moderately abnormal blood cell counts, and 3 had skin erosions. In 3 patients, methotrexate dosage or dosing-schedule errors were identified. No other contributing factors (eg, renal dysfunction or interacting drugs) were identified. Mucocutaneous biopsy specimens consistently showed multiple dystrophic keratinocytes. Limitations We studied only 5 patients and obtained no sensitivity or specificity data on the diagnostic value of keratinocyte dystrophy. Conclusion Keratinocyte dystrophy may help to diagnose skin toxicity of low-dose methotrexate, even in the absence of known risk factors or methotrexate administration errors. Studies of the diagnostic performance of this histologic sign are needed.