We conducted a study on building-related respiratory disease and associated social impact in an office building with water incursions in the northeastern United States. An initial questionnaire had 67% participation (888/1,327). Compared with the U.S. adult population, prevalence ratios were 2.2-2.5 for wheezing, lifetime asthma, and current asthma, 3.3 for adult-onset asthma, and 3.4 for symptoms improving away from work (p < 0.05). Two-thirds (66/103) of the adult-onset asthma arose after occupancy, with an incidence rate of 1.9/1,000 person-years before building occupancy and 14.5/1,000 person-years after building occupancy. We conducted a second survey on 140 respiratory cases, 63 subjects with fewer symptoms, and 44 comparison subjects. Health-related quality of life decreased with increasing severity of respiratory symptoms and in those with work-related symptoms. Symptom status was not associated with job satisfaction or how often jobs required hard work. Respiratory health problems accounted for one-third of sick leave, and respiratory cases with work-related symptoms had more respiratory sick days than those without work-related symptoms (9.4 vs. 2.4 days/year; p < 0.01). Abnormal lung function and/or breathing medication use was found in 67% of respiratory cases, in 38% of participants with fewer symptoms, and in 11% of the comparison group (p < 0.01), with similar results in never-smokers. Postoccupancy-onset asthma was associated with less atopy than preoccupancy-onset asthma. Occupancy of the water-damaged building was associated with onset and exacerbation of respiratory conditions, confirmed by objective medical tests. The morbidity and lost work time burdened both employees and employers.