© 2019 The Author(s) 2019. The association of historical opioid use with health care use and death among patients with chronic obstructive pulmonary disease (COPD) has been tested. Using Mississippi Medicaid data, we examined the association of transient or short-term opioid use and acute respiratory exacerbations among adults with COPD. We used a case-crossover design and 2013-2017 Mississippi Medicaid administrative claims data. A total of 1,972 qualifying exacerbation events occurred in 1,354 beneficiaries. The frequency and dose of opioid exposure in the 7 days before the exacerbation were examined and compared with the opioid exposure in 10 control windows, each 7 days long, before the exacerbation. Adjusted odds ratios were estimated using conditional logistic regression models to estimate the risk of opioid use on exacerbations after accounting for use of bronchodilators, corticosteroids, benzodiazepines, and β-blockers. Overall, opioid exposure in the 7 days before an exacerbation was significantly associated with acute respiratory exacerbation (odds ratio = 1.81; 95% confidence interval: 1.60, 2.05). Each 25-mg increase in morphine equivalent daily dose was associated with an 11.2% increase in the odds of an acute respiratory exacerbation (odds ratio = 1.11; 95% confidence interval: 1.04, 1.20). Transient use of opioids was significantly associated with acute respiratory exacerbation of COPD.