Background: Nonspecific building-related symptoms among occupants of modern office buildings worldwide are common and may be associated with important reductions in work performance, but their etiology remains uncertain. Characteristics of heating, ventilating, and air-conditioning (HVAC) systems in office buildings that increase risk of indoor contaminants or reduce effectiveness of ventilation may cause adverse exposures and subsequent increase in these symptoms among occupants.Methods: We analyzed data collected by the U.S. Environmental Protection Agency (EPA) from a representative sample of 100 large U.S. office buildings -the Building Assessment and Survey Evaluation (BASE) study -using multivariate-adjusted logistic regression models with generalized estimating equations. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between seven building-related symptom outcomes and selected HVAC system characteristics (excluding ventilation rate, analyzed elsewhere) in the 97 airconditioned study buildings.Results: Among factors of HVAC design or configuration: Outdoor air intakes less than 60 m above the ground were associated with substantially increased odds of most symptoms assessed (ORs up to 2.7). Among factors of HVAC condition, maintenance, or operation: the presence of humidification systems in good condition was associated with reduction in skin symptoms (OR=0.5), whereas the presence of humidification systems in poor condition was associated with increases in upper respiratory symptoms, eye symptoms, fatigue/difficulty concentrating, and skin symptoms (ORs=1.5 to 1.7). Lack of regularly scheduled inspections for HVAC components was associated with increased eye and upper respiratory symptoms (ORs=2.2, 1.6). Less frequent cleaning of cooling coils or condensate drain pans was associated with increased headache and eye symptoms (ORs=1.5, 1.5). Ventilation for 10-12 hours per day (relative to more) was associated with a general slight increase in symptoms, especially fatigue/difficulty concentrating (OR=1.3). Several specific associations opposite of predicted were found, such as with cleanliness of air handler components and operational condition of air handling components. Discussion: Most of the many potential risk factors assessed here had not been investigated previously, and associations found with single symptom groups may have been by chance, including some that were the reverse of expected. Risk factors newly identified in these analyses that deserve attention include outdoor air intakes less than 60 m above the ground (which were correlated with higher levels of some outdoor vehicle-emitted pollutants), poorly maintained humidification systems, and lack of scheduled inspection for HVAC systems. Infrequent cleaning of cooling coils and drain pans were associated with increases in several symptoms in these as well as prior analyses of BASE data. Replication of these findings is needed, using more objective measurements of both exposure and health response. Co...