BACKGROUND Numerous reports of drug interactions exist, yet not all are valid in or pertinent to dentistry. This article provides an overview of drug interactions with analgesics and identifies those that are clinically relevant. METHODS The author reviewed reports of drug interactions involving nonsteroidal anti-inflammatory drugs, or NSAIDs (including aspirin), acetaminophen and opioids to determine the interactions' validity and clinical relevance. Consistent with the practice followed in other articles in this series, the author determined the significance of the proposed interaction by gauging its reported severity and the quality of the documentation. CONCLUSIONS NSAIDs should not be taken by patients taking high-dose methotrexate, anticoagulants or alcohol. They should be avoided in elderly or renally impaired patients taking digoxin, and avoided over the long term in those taking other NSAIDs. It is possible that NSAIDs should not be given to patients taking lithium, but future studies should be conducted to confirm this. Use of NSAIDs likely is appropriate in the short term with patients taking antihypertensives, unless they have severe congestive heart disease. Aspirin should not be given to patients taking oral hypoglycemics, valproic acid or carbonic anhydrase inhibitors. Acetaminophen may be given in the short term to any patient with a healthy liver, but it should not be given to a patient who has stopped drinking alcohol after chronic intake. Opioids should not be combined with alcohol, and meperidine must be avoided in the patient who has taken monoamine oxidase inhibitors in the previous 14 days. CONCLUSIONS Drug interactions with analgesics are often reported, but only a small number have clinical relevance in dentistry. Awareness of the significance of these interactions will allow dentists to prescribe analgesics optimally and minimize the potential for adverse reactions.