Objective  To evaluate the agreement among drug–drug interaction (DDI) compendia as to designation of interactions as having the greatest clinical importance (“major” DDIs).

Design  Cross-sectional, one-time evaluation.

Setting  United States in fall 2001.

Participants  Not applicable.

Interventions  Major DDIs involving prescription medications likely to be dispensed in the community and ambulatory pharmacy settings were identified as listed in four compendia that provide specific, detailed information about DDIs (Drug Interaction Facts, Drug Interactions: Analysis and Management, Evaluations of Drug Interactions, and the MicroMedex DRUG-REAX program).

Main Outcome Measure  Level of agreement between DDI compendia as assessed by the intraclass correlation coefficient (ICC).

Results  Overall, 406 major DDIs were listed in one or more of the four compendia. Only 9 (2.2%) of these major DDIs were listed in all four compendia; in fact, the majority of interactions were listed in only one compendium (291 DDIs, 71.7%), despite these interactions being considered of greatest clinical relevance by at least one compendium. The ICC among the compendia was −0.092, indicating low agreement on the classification of major DDIs.

Conclusion  Little agreement exists among commonly used drug interaction compendia for DDIs that were classified in fall 2001 as having the highest clinical relevance and importance. A concerted effort to identify DDIs of the highest clinical importance is needed to design effective strategies to avoid and manage them.