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. Most reported research into environmental risk factors for these symptoms has focused on ventilation system-related factors, dampness, and particle removal through filtration and cleaning, with relatively few studies of other potential sources of indoor contaminants. 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 a diverse set of potential indoor and outdoor sources for indoor pollutants. Results: Although most of the investigated risk factors showed no apparent association with building-related symptoms, some interesting associations resulted. Increased prevalence of symptoms was associated with carpets older than one year (lower respiratory symptoms), non-carpeted floors (upper and lower respiratory symptoms), older furniture (eye and skin symptoms), infrequent vacuuming (upper respiratory, eye, and skin symptoms and headache), and masonry exterior walls (cough, eye symptoms, and fatigue/concentration difficulty). Discussion: For the many potential risk factors assessed, almost none had been investigated previously, and many associations found here may have been by chance. Additional confirmatory research focused on risk factors initially identified here is needed, using more objective measures of health outcomes and risk factors or exposures.