IMPORTANCE: Exposure to disinfectants in health care workers has been associated with respiratory health outcomes, including asthma. Despite the biological plausibility of an association between disinfectants (irritant chemicals) and risk of chronic obstructive pulmonary disease (COPD), available data are sparse. OBJECTIVE: To investigate the association between exposure to disinfectants and COPD incidence in a large cohort of US female nurses. DESIGN, SETTING, AND PARTICIPANTS: The Nurses' Health Study II is a US prospective cohort study of 116 429 female registered nurses from 14 US states who were enrolled in 1989 and followed up through questionnaires every 2 years since. The present study included women who were still in a nursing job and had no history of COPD in 2009, and used data from the 2009 through 2015 questionnaires. Clean and complete data used for this analysis were available in July 2018, and analyses were conducted from September 2018 through August 2019. EXPOSURES: Occupational exposure to disinfectants, evaluated by questionnaire and a job-task-exposure matrix (JTEM). MAIN OUTCOMES AND MEASURES: Incident physician-diagnosed COPD evaluated by questionnaire. RESULTS: Among the 73 262 women included in the analyses, mean (SD) age at baseline was 54.7 (4.6) years and 70 311 (96.0%) were white, 1235 (1.7%) black, and 1716 (2.3%) other; and 1345 (1.8%) Hispanic, and 71 917 (98.2%) non-Hispanic. Based on 368 145 person-years of follow-up, 582 nurses reported incident physician-diagnosed COPD. Weekly use of disinfectants to clean surfaces only (16 786 [22.9%] of participants exposed) and to clean medical instruments (13 899 [19.0%] exposed) was associated with COPD incidence, with adjusted hazard ratios of 1.38 (95% CI, 1.13-1.68) for cleaning surfaces only and 1.31 (95% CI, 1.07-1.61) for cleaning medical instruments after adjustment for age, smoking (pack-years), race, ethnicity, and body mass index. High-level exposure, evaluated by the JTEM, to several specific disinfectants (ie, glutaraldehyde, bleach, hydrogen peroxide, alcohol, and quaternary ammonium compounds) was significantly associated with COPD incidence, with adjusted hazard ratios ranging from 1.25 (95% CI, 1.04-1.51) to 1.36 (95% CI, 1.13-1.64). Associations were not modified by smoking or asthma status (P for interaction > .15). CONCLUSIONS AND RELEVANCE: These longitudinal results suggest that regular use of chemical disinfectants among nurses may be a risk factor for developing COPD. If future studies confirm these results, exposure-reduction strategies that are compatible with infection control in health care settings should be developed.