People who are anxious about their health are more likely to misinterpret health information as personally threatening and less likely to be reassured by medical investigations that show they are free from disease. Consequently, health anxious people would be expected to react more adversely to cancer screening, but this possibility has rarely been explored. The moderating role of health anxiety on the psychological impact of participating in colorectal cancer screening was examined among a sub-sample of 3535 participants in a large, community-based trial of colorectal cancer screening in the UK. The screening modality was flexible sigmoidoscopy, which examines the bowel for pre-cancerous polyps. It was predicted that health anxiety would be associated with more worry about cancer before screening, a greater increase in worry if polyps were detected, and less reassurance after a clear result. As expected, health anxious participants were more anxious and more worried about bowel cancer both before and after screening. However, they experienced greater reductions in anxiety and worry about cancer following the examination. They reported lower levels of reassurance following screening, but also expressed more positive reactions to the experience. The positive psychological benefits of attending medical investigations should be examined in future work, because this may go some way towards explaining why health anxious people repeatedly seek medical interventions.