Exposure to microgravity during spaceflight is known to elicit orientation illusions, errors in sensory localization, postural imbalance, changes in vestibulo-spinal and vestibulo-ocular reflexes, and space motion sickness. The objective of this experiment was to investigate whether an alteration in cognitive visual-spatial processing, such as the perception of distance and size of objects, is also taking place during prolonged exposure to microgravity. Our results show that astronauts on board the International Space Station exhibit biases in the perception of their environment. Objects’ heights and depths were perceived as taller and shallower, respectively, and distances were generally underestimated in orbit compared to Earth. These changes may occur because the perspective cues for depth are less salient in microgravity or the eye-height scaling of size is different when an observer is not standing on the ground. This finding has operational implications for human space exploration missions.