Associations between environmental factors and work-related health conditions were assessed using regression techniques with environmental and health data for 2435 respondents in 80 office buildings included in the National Institute for Occupational Safety and Health Health Hazard Evaluation program. The health conditions analyzed included two symptom groupings—multiple lower respiratory symptoms and multiple atopic symptoms—and the presence of asthma diagnosed after beginning work in the building. Four categories of environmental variables were included: heating, ventilation, and air conditioning (HVAC) system design; HVAC maintenance; building design; and building maintenance. Female gender and age over 40 years showed increased relative risks (RRs) for each health condition. In regression models adjusted for age and gender, RRs of multiple lower respiratory symptoms were increased for variables in the HVAC design and maintenance categories, with the highest RR for presence of debris inside the air intake [RR = 3.1, confidence interval (CI) = 1.8, 5.2] and for poor or no drainage from drain pans (RR = 3.0, CI = 1.7, 5.2). Elevated RRs of multiple atopic symptoms were found for variables in three of the four environmental categories, with the highest for presence of suspended ceiling panels (RR = 2.3, CI = 1.0, 5.5). The RR of asthma was highest if recent renovation with new drywall had been performed (RR = 2.5, CI = 1.4, 4.5). These data are from office spaces about which there was some level of occupant concern, and thus it may not be appropriate to use them to estimate the magnitude and distribution of symptoms found in all office spaces within U.S. buildings. Furthermore, the high degree of correlation among environmental variables makes it difficult to disentangle which are the most important predictors of work-related health conditions. The analysis is useful, however, for determining factors that may be associated with development of health conditions in the office environment and which might be considered in any building plan to reduce indoor air-related symptoms.