Diisocyanates, a group of highly reactive chemicals, have frequently been associated with occupational asthma. We evaluated respiratory health in workers at a new wood products manufacturing plant that uses methylene diphenyl diisocyanate (MDI), and was designed and operated with a goal of minimizing worker exposures. Health surveys using standardized respiratory questionnaires were done prior to the initial use of diisocyanates in the plant, and semiannually thereafter for a period of 2 years. Other testing included occupational and work practice histories, serial peak flow measurements, spirometry, methacholine challenge, and measurement of specific IgE antibodies to MDI-albumin conjugate. Of 214 plant employees who participated in at least one health survey, a follow-up survey was also available from 178 employees (83%). New-onset asthma-like symptoms (NAS) were reported by 15 of 56 workers (27%) in areas with the highest potential for exposures to liquid MDI monomer and prepolymer, vs 0 of 43 workers in the lowest potential exposure areas (p = 0.001). In the areas with high potential exposure, NAS developed in 47% of workers who had noted MDI skin staining, vs 19% without skin stains (p = 0.07). Working around and cleaning up liquid MDI represented a significant risk for asthma-like symptoms in both current smokers and nonsmokers; work with finished wood products did not. Asthma-like symptoms were associated with variable airflow limitation (odds ratio [OR], 5.0; confidence interval [CI], 1.4 to 18.7) and specific IgE to MDI-albumin (OR, 3.2; CI, 1.1 to 9.0), but not with skin prick tests to common aeroallergens (OR, 1.1; CI, 0.5 to 2.7). During the first 2 years of operation, in a plant designed and operated to control exposure to diisocyanates, the development of asthma-like symptoms was reported in a relatively high proportion of the employees who worked with liquid MDI. To prevent asthma symptoms among workers, careful control of respiratory tract exposures associated with liquid MDI is important, especially during cleanup activities. Strict limitation of skin contact with diisocyanates may also be necessary.