Thirty years of public health research have demonstrated that improved indoor environmental quality is associated with better health outcomes. Recent research has demonstrated an impact of the indoor environment on cognitive function. We recruited 109 participants from 10 high-performing buildings in five U.S. cities. In each city, buildings were matched by week of assessment, tenant, type of worker and work functions. A key distinction between the matched buildings was whether they had achieved green certification. Workers were administered a cognitive function test of higher order decision-making performance twice during the same week while indoor environmental quality parameters were monitored. Workers in green certified buildings scored 26.4% higher on cognitive function tests, controlling for annual earnings, job category and level of schooling, and had 30% fewer sick building symptoms than those in non-certified buildings. These outcomes may be partially explained by IEQ factors, including thermal conditions and lighting, but the findings suggest that the benefits of green certification standards go beyond measureable IEQ factors. We describe a holistic “buildingomics” approach for examining the complexity of factors in a building that influence human health.