Background: Flexible sigmoidoscopy is usually performed without sedation in screening programs for colorectal cancer. Most patients report some degree of discomfort or pain during the procedure. The aim of this study was to evaluate self-administered nitrous oxide as a method to reduce patient discomfort, thereby improving the procedure and conceivably increasing patient compliance and motivation. Methods: In a double-blind, randomized, placebo-controlled study, 38 patients undergoing sigmoidoscopy self- administered 60% nitrous oxide (n = 18) or oxygen (n = 20) by mask. The endoscopist recorded the depth of insertion of the sigmoidoscope, duration of the procedure, and time to patient recovery. Patients scored the degree of pain and discomfort felt during the examination. Results: There were no significant differences between the groups with regard to patients' age, gender, pain or discomfort, duration of procedure, or depth of insertion. Recovery time was significantly longer in the nitrous oxide group (3.3 ± 0.6 minutes vs 0.5 ± 0.5 minutes; p = 0.02), but this finding was of no practical or clinical consequence. Conclusions: The addition of 'on demand' nitrous oxide did not improve sigmoidoscopy performance or diminish pain and discomfort. However, further studies using improved administration techniques and larger study groups are justified in the search for ways to increase compliance with and motivation for colorectal cancer screening.