OBJECTIVE: To report a possible pharmacogenomics (PGx)-related, cognitive dysfunction, adverse drug reaction from methotrexate (MTX) that may be multifactorial in origin. SUMMARY: The patient subject is a 76-year-old Caucasian female of Russian ancestry suffering from rheumatoid arthritis and treated with MTX who presented to the diagnostic and consultative physician service in a medical clinic with advancing cognitive dysfunction, manifesting as memory loss, dizziness, and confusion. Components of this possible adverse drug reaction (ADR) may include ancestry, pharmacogenomics (PGx) characteristics of the patient, and a change in route of administration, among others. The case demonstrates how patients referred to a pharmacist consult service for a suspected ADR with possible PGx implications may uncover other contributory factors to the ADR. CONCLUSION: PGx testing may increase clinical pharmacist referrals to identify a PGx etiology to an ADR. However, they may also identify other non-PGx contributory factors to an ADR.