BACKGROUND The aim of this study was to compare the effect of topical glycerol trinitrate ointment (GTN) with topical diltiazem hydrochloride ointment (DTZ) in the treatment of chronic anal fissure. METHODS Prospectively, 102 patients were treated randomly with either GTN ointment (0.2%) or DTZ ointment (2%) a couple of times daily for 12 weeks. RESULTS Forty-five patients (88.2%) in group DTZ and 36 patients (70.6%) in group GTZ had a reduction of symptoms. The decrease in the symptoms for group DTZ was significantly more than for group GTN (P = 0.02). Mean time for symptom reduction was 2.44 +/- 0.30 in group DTZ and 2.50 +/- 0.28 weeks in group GTN with no significant differences between the two groups (P > 0.05). Complete relief of symptoms was observed in 72.5% and 54.9% patients in groups DTZ and GTN, respectively. The frequency of complete relief of symptoms between the two groups was not significant (P > 0.05). Complete remission of anal fissure occurred in 66.7% patients in group DTZ and 54.9% patients in group GTN, which shows no significant difference. Mean time taken for fissure healing in the GTN group was dramatically less than in the DTZ group (P = 0.001). Finally, 33.3% of patients in the DTZ group and 45.1% of patients in the GTN group underwent operation. The need for operation was not significantly different between the two groups (P > 0.05). CONCLUSIONS Both DTZ and GTN are equally effective and can be the preferred first-line treatment of chronic anal fissure. However, GTN is associated with a higher rate of headache, and should be replaced by DTZ.