Higher indoor concentrations of air pollutants due, in part, to lower ventilation rates are a potential cause of sick building syndrome (SBS) symptoms in office workers. The indoor carbon dioxide (CO2) concentration is an approximate surrogate for indoor concentrations of other occupant-generated pollutants and for ventilation rate per occupant. Using multivariate logistic regression (MLR) analyses, we evaluated the relationship between indoor CO2 concentrations and SBS symptoms in occupants from a probability sample of 41 U.S. office buildings. Two CO2 metrics were constructed: average workday indoor minus average outdoor CO2 (dCO2, range 6-418 ppm), and maximum indoor 1-h moving average CO2 minus outdoor CO2 concentrations (dCO2MAX). MLR analyses quantified dCO2/SBS symptom associations, adjusting for personal and environmental factors. A dose-response relationship (p < 0.05) with odds ratios per 100 ppm dCO2 ranging from 1.2 to 1.5 for sore throat, nose/sinus, tight chest, and wheezing was observed. The dCO2MAX/SBS regression results were similar.