OBJECTIVES: Recent nested case-control studies have raised concerns of the risk for acute urinary retention (AUR) among patients receiving tiotropium, a long-acting inhaled anticholinergic. In this study, we examined the effect of inhaled anticholinergics on the occurrence of AUR using self-controlled methods, case-crossover and case-time-control designs, which adjust for all time-invariant confounders and reduce threat of control-selection bias. METHODS: Patients aged ≥45 years with chronic obstructive pulmonary disease (COPD) were included from the IMS LifeLink Health Plan Claims Databases. Cases with AUR in both inpatient and outpatient settings during 2006-2009 were identified. In the case-time-control approach, ten controls were randomly selected for each case after matching age, gender, geographic location, to control for the secular trend of medication use. Exposure to tiotropium, ipratropium, and medications with significant anticholinergic effects was determined in the 30-day period prior to the event and in a 30-day reference period which was 180 days prior. Multivariate conditional logistic regression was used to evaluate the association between anticholinergic exposure and AUR, with sensitivity analyses and subgroup analyses based on age, gender and related comorbidities. RESULTS: A total of 6,008 cases and 60,080 controls were identified. The mean age was 74 years and ~78% were male. In the case-crossover analysis, adjusted odds ratio (OR) of AUR was 1.34 (95%CI 1.13-1.60) for tiotropium and 1.19 (1.00-1.41) for ipratropium. In the case-time-control analysis, the risk of AUR OR was 1.24 (1.03-1.50) for tiotropium and 1.26 (1.05-1.51) for ipratropium. The AUR risk related to tiotropium and ipratropium was similar among patients aged >75 years, males, and those with benign prostate hyperplasia, prostate cancer, and diabetes. CONCLUSIONS: Our results support current evidence that use of inhaled anticholinergics is associated with higher risk for AUR (odds increased by 20-35%) in COPD patients. Providers should be aware of the potential risk for AUR when making treatment decisions.