Background: We sought to determine whether premedication for colonoscopy with intravenous hyoscyamine sulfate (Levsin) was helpful from the standpoint of the colonoscopist and the patient. Methods: One hundred sixteen adult patients were randomized to receive either 0.5 mg hyoscyamine sulfate intravenous (n = 57) or placebo (n = 59). After administration of study drug, patients were given meperidine and midazolam. Parameters measured included the time required to reach the cecum, total procedure time, and the endoscopist's perception of the adequacy of sedation, difficulty of insertion, and amount of colonic spasm on insertion and withdrawal. Patients were given a postprocedure questionnaire assessing their experience. Results: In patients receiving hyoscyamine, there was a shorter cecal intubation time (median 9.2 vs. 12.9 minutes; p = 0.01), shorter total colonoscopy time (median 20.5 vs. 25.0 minutes; p = 0.01), better patient sedation (p = 0.02), easier colonic insertion (p = 0.001), and less spasm on insertion (p = 0.01). No difference was found in the amount of spasm during withdrawal or the total dosages of meperidine or midazolam used. Patients receiving hyoscyamine sulfate reported being more comfortable during their procedures (p < 0.001) and were more willing to repeat colonoscopy in the future (p = 0.0001). The only adverse effect seen during the study was a 27% incidence of sinus tachycardia that occurred in patients receiving hyoscyamine. Conclusions: Premedication with intravenous hyoscyamine sulfate was beneficial in terms of the time required for cecal intubation, total procedure time, adequacy of sedation, and scales of patient comfort. However, the high frequency of sinus tachycardia seen with the dose used in our study, which was extremely rapid in two patients, indicates the need for further study before the drug can be recommended as a routine premedication for colonoscopy.