Occupants of office buildings are exposed to low concentrations of complex mixtures of volatile organic compounds (VOCs) that encompass a number of chemical classes and a broad range of irritancies. “Sick building syndrome” (SBS) is suspected to be related to these exposures. Using data from 22 office areas in 12 California buildings, seven VOC exposure metrics were developed and their ability to predict self-reported SBS irritant symptoms of office workers was tested. The VOC metrics were each evaluated in a multivariate logistic regression analysis model adjusted for other risk factors or confounders. Total VOCs and most of the other metrics were not statistically significant predictors of symptoms in crude or adjusted analyses. Two metrics were developed using principal components (PC) analysis on subsets of the 39 VOCs. The Irritancy/PC metric was the most statistically significant predictor of adjusted irritant symptoms. The irritant potencies of individual compounds, highly correlated nature of indoor VOC mixtures, and probable presence of potent, but unmeasured, VOCs were variously factored into this metric. These results, which for the first time show a link between low level VOC exposures from specific types of indoor sources to SBS symptoms, require confirmation using data sets from other buildings.