Reactive oxygen species (ROS) are an essential component of the host defense against fungal infections. However, little is known about how common genetic variation affects ROS-mediated antifungal host defense. In the present study, we investigated the genetic factors that regulate ROS production capacity in response to the two human fungal pathogens: Candida albicans and Aspergillus fumigatus. We investigated fungal-stimulated ROS production by immune cells isolated from a population-based cohort of approximately 200 healthy individuals (200FG cohort), and mapped ROS-quantitative trait loci (QTLs). We identified several genetic loci that regulate ROS levels (P < 9.99 × 10-6), with some of these loci being pathogen-specific, and others shared between the two fungi. These ROS-QTLs were investigated for their influence on the risk of invasive pulmonary aspergillosis (IPA) in a disease relevant context. We stratified hematopoietic stem-cell transplant (HSCT) recipients based on the donor's SNP genotype and tested their impact on the risk of IPA. We identified rs4685368 as a ROS-QTL locus that was significantly associated with an increased risk of IPA after controlling for patient age and sex, hematological malignancy, type of transplantation, conditioning regimen, acute graft-versus-host-disease grades III-IV, and antifungal prophylaxis. Collectively, this data provides evidence that common genetic variation can influence ROS production capacity, and, importantly, the risk of developing IPA among HSCT recipients. This evidence warrants further research for patient stratification based on the genetic profiling that would allow the identifications of patients at high-risk for an invasive fungal infection, and who would benefit the most from a preventive strategy.