The possible benefits of premedication with the antispasmodic hyoscine n-butyl bromide (hyoscine) and analgesia with inhaled nitrous oxide/oxygen mixture (nitrous oxide) were assessed in a double-blinded, placebo-controlled trial. Consecutive patients at normal risk for cancer undergoing screening flexible sigmoidoscopy were randomly allocated to receive either (1) intravenous hyoscine 20 mg plus inhaled oxygen on demand (n = 40), (2) sterile water injection plus inhaled nitrous oxide on demand (n = 48), or (3) sterile water injection plus inhaled oxygen on demand (n = 43). One recently trained primary care physician performed all procedures. Duration of the procedure, endoscopic findings, and depth of insertion were recorded. After the examination, screenees rated their degree of pain during the procedure using a visual analogue scale. Depth of insertion did not differ between the three study groups, but the duration of the procedure was significantly less in the hyoscine group (median, 12.5 minutes) as compared with placebo (median, 18 minutes; p = .0008). Fifty-four percent of screenees chose to use the on-demand gas. Pain scores were significantly lower in those individuals who inhaled nitrous oxide as compared with placebo (p = .045). Premedication with antispasmodic shortens total procedure time for flexible sigmoidoscopy by a moderately experienced endoscopist as compared with placebo. In this study, a significant number of screenees experienced discomfort during flexible sigmoidoscopy, which appeared to be reduced by offering nitrous oxide inhalation.