OBJECTIVE: The objective of this review is to systematically analyze the prospective randomized controlled trials on the effectiveness of diltiazem (DTZ) and glyceryltrinitrate (GTN) for the pharmacological management of chronic anal fissure (CAF). MATERIALS AND METHODS: A systematic review of the literature was undertaken. Prospective randomized controlled trials on the effectiveness of DTZ for the management of CAF were selected according to specific criteria and analyzed to generate summative data. RESULTS: Five studies encompassing 263 patients with CAF were retrieved from the electronic databases. Only two randomized controlled trials on 103 patients qualified for the meta-analysis. There were 53 patients in the DTZ group and 50 patients in the GTN group. Both DTZ and GTN were equally effective for the treatment of CAF (random-effect model risk ratio [RR] 0.29 [90.06-1.33] 95% confidence interval [CI], z=0.62, p=0.536). However, there was significant heterogeneity between the trials. GTN was associated with higher side effects rate (fixed-effect model RR 0.45 [0.28-0.73] 95% CI, z= -3.22, p=0.001) and higher headache rate (fixed-effect model RR 0.33 [0.17-0.64] 95% CI, z= -3.27, p=0.001) as compared to DTZ. There was no statistically significant recurrence rate of CAF between two pharmacotherapies (fixed-effect model RR 0.66 [0.18-2.41] 95% CI, z= -0.62, p=0.535). CONCLUSION: Both DTZ and GTN are equally effective and can be used for the management of CAF. However, GTN is associated with a higher rate of side effects (headache/anal irritation), and it should be replaced by DTZ. The recurrence rate of CAF after the use of both pharmacotherapies is equal.