Compact waveguide-based photobioreactors with high surface area-to-volume ratios and optimum light-management strategies have been developed to achieve high volumetric productivities within algal cultures. The light-managing strategies have focused on optimizing sunlight collection, sunlight filtration, and light delivery throughout the entire bioreactor volume by using light-directing waveguides. In addition to delivering broad-spectrum or monochromatic light for algal growth, these systems present an opportunity for advances in photobioreactor disinfection by using germicidal ultraviolet (UV) light. Here, we investigated the efficacy of in situ, nonchemical UV treatment to disinfect a heterotrophic contaminant in a compact photobioreactor. We maintained a >99% pure culture of Synechocystis sp. PCC 6803 for an operating period exceeding 3 weeks following UV treatment of an intentionally contaminated waveguide photobioreactor. Without UV treatment, the culture became contaminated within only a few days (control). We developed a theoretical model to predict disinfection efficiency based on operational parameters and bioreactor geometry, and we verified it with experimental results to predict the disinfection efficiency of a Bacillus subtilis spore culture.