Objective The objective of this study is to explore whether the use of medications that antagonize mediators of inflammatory responses reduces the risk of delirium in older adults. Methods A nested case–control study was conducted using data from a prospective study of delirium in older long‐term care residents from 7 long‐term care facilities in Montreal and Quebec City, Canada. The Confusion Assessment Method was used to diagnose incident delirium. The use of medications that antagonize mediators of inflammatory responses was determined by examining facility pharmacy databases and coding medications received daily by each resident. Risk sets were built using incidence density sampling: each risk set consisted of a case with incident delirium and all controls without incident delirium at the same date and facility. Conditional logistic regression was used to assess the association of exposure to inflammation antagonist medications with the incidence of delirium. Results Of 254 residents, 95 developed incident delirium during 24 weeks (cases); each case was matched with up to 35 controls. Unadjusted and adjusted odds ratios (95% CI) of delirium for residents exposed to at least one inflammation antagonist medication were 0.53 (0.34, 0.81) and 0.60 (0.38, 0.92), respectively. Estimates of the risk of incident delirium associated with specific medications and medication classes were mostly protective but not statistically significant. Conclusion The use of medications that antagonize mediators of inflammatory responses may reduce the risk of delirium in older adults. Despite study limitations, the findings merit further investigation using larger patient samples, more precise measures of exposure and better control of potential confounding variables. Copyright © 2016 John Wiley & Sons, Ltd.