Background: Chronic anal fissure is a common disease that is accompanied with pain and bleeding during defecation. Various surgical and non-surgical methods have been offered for the treatment of this condition. The aim of this randomised clinical study was to compare the effectiveness and safety of nifedipine and isosorbide dinitrate (ISDN) in the treatment of chronic anal fissure. Methods: This double-blind clinical trial study was performed on patients aged 20 to 60 years old in 2012 to 2013. The samples with a primary diagnosis of chronic anal fissure were enrolled from the patients admitted to public treatment at the educational Imam Ali Clinic, Shahrekord, Iran by researchers and general surgery specialists. The patients were randomised into two groups: nifedipine 0.3% (n = 35) or ISDN 0.2% (n = 35) applied three times a day for three weeks. The patients were examined on the 7th, 14th, and 21st days of treatment, and the symptoms including bleeding, pain, and healing status, as well as the side effects of the drugs, were assessed. Pain was evaluated using a visual analogue scale (VAS). Results: After 21 days of follow-up, complete healing was achieved in 77.1% (n = 27) of patients in the nifedipine group and 51.4% (n = 18) in the ISDN group (P = 0.05). The mean VAS of the pain on day 21 was 0.91 (SD 0.01) in the ISDN group and 0.45±0.78 in the nifedipine group, with a statistically significant difference (P = 0.038). The bleeding was similar in the two groups (P = 0.498). Conclusion: In view of the findings on healing status and pain in the patients, nifedipine may be significantly more effective in the treatment of chronic anal fissure than ISDN.