The cause of Sick Building Syndrome has attracted worldwide attention. Studies on the correlation between indoor air pollution and SBS symptoms are still limited. A cross-sectional study was conducted to investigate the prevalence of sick building syndrome symptoms and its associated factors among residents in Nanjing, China. 1281 residents participated in a questionnaire survey, and information on their dwelling building characteristics, home environmental factors, lifestyles and sick building symptoms was obtained. Indoor PM2.5 concentrations were modeled by the multizone airflow and contaminant transport program. The prevalence of general, mucosal and dermal symptoms were 14.4%, 9.5% and 5.1%, respectively. Females, residents with respiratory disease history and from lower income families, reported more sick building syndrome symptoms. Painting peeling, indoor PM2.5 concentration and environmental smoking exposure were significantly associated with general symptoms. Residents’ satisfaction with the indoor environment was a significant predictor of sick building syndrome symptoms. Ventilation by opening windows for more than 6 h per day was found to be a protective factor for mucosal and dermal symptoms. Besides this, residential building characteristics such as building construction year, floor area were also associated with dermal symptoms. The study indicates that improving indoor environmental quality and keeping good lifestyle habits are important to prevent residents suffering from sick building syndrome symptoms.