This study investigated whether urinary 8-hydroxydeoxyguanosine (8-OHdG), a biomarker of oxidative stress, was associated with indoor air quality for non-smokers in high-rise building offices. With informed consents, urine samples from 344 non-smoking employees in 86 offices were collected to determine 8-OHdG concentrations. The concentrations of carbon dioxide (CO2) and total volatile organic compounds (TVOCs) in each office and outside of the building were simultaneously measured for eight office hours. The average workday difference between indoor and outdoor CO2 concentrations (dCO2) was used as a surrogate measure of the ventilation efficiency for each office unit. The CO2 levels in the offices ranged 467–2810 ppm with a mean of 1170 ppm, or 2.7 times higher than that in the outside air. The average urinary 8-OHdG levels among employees increased from 3.10 μg/g creatinine, for those at the lowest tertile levels of both dCO2 and TVOCs, to 6.27 μg/g creatinine, for those at the highest tertile levels. Multivariate logistic regression analysis showed that the risk of having the urinary 8-OHdG level of greater than the median, 4.53 μg/g creatinine, for participants was increased significantly at the highest tertile dCO2 level of >680 ppm (odds ratio (OR)=3.37, 95% confidence interval (CI)=1.20–9.46). The effect was significant at the middle tertile TVOCs level of 114–360 ppb (OR=2.62, 95% CI=1.43–4.79), but not at the highest tertile. Inadequate ventilation in office increases the risk of building-related oxidative stress in non-smoking employees.