Invasive lionfish are assumed to significantly affect Caribbean reef fish communities. However, evidence of lionfish effects on native reef fishes is based on uncontrolled observational studies or small-scale, unrepresentative experiments, with findings ranging from no effect to large effects on prey density and richness. Moreover, whether lionfish affect populations and communities of native reef fishes at larger, management- relevant scales is unknown. The purpose of this study was to assess the effects of lionfish on coral reef prey fish communities in a natural complex reef system. We quantified lionfish and the density, richness, and composition of native prey fishes (0–10 cm total length) at sixteen reefs along ∼250 km of the Belize Barrier Reef from 2009 to 2013. Lionfish invaded our study sites during this four-year longitudinal study, thus our sampling included fish community structure before and after our sites were invaded, i.e., we employed a modified BACI design. We found no evidence that lionfish measurably affected the density, richness, or composition of prey fishes. It is possible that higher lionfish densities are necessary to detect an effect of lionfish on prey populations at this relatively large spatial scale. Alternatively, negative effects of lionfish on prey could be small, essentially undetectable, and ecologically insignificant at our study sites. Other factors that influence the dynamics of reef fish populations including reef complexity, resource availability, recruitment, predation, and fishing could swamp any effects of lionfish on prey populations.