Endodontic post-treatment pain is one of the significant problems faced by the dentist. In patients with necrotic teeth and acute apical periodontitis inter-appointment pain during root canal treatment is a common finding. The objective of the study is to compare the efficacy of Ledermix paste and Calcium hydroxide on inter-appointment pain during root canal treatment in patients with acute apical periodontitis. In this comparative prospective study trial, sixty patients who were undergoing dental treatment in Islamic international dental hospital, Islamabad were selected after fulfilling the inclusion and exclusion criteria. All patients were randomly allocated in two groups. Group 1: consists of 30 patients and were treated with Ledermix paste while Group 2: include 30 patients treated with Calcium hydroxide for inter-appointment pain during root canal treatment. All Patients were interviewed regarding pain during the inter-appointment period. Visual analogue scale (VAS) was used to record pain in every patient. Independent samples t-test was used to compare mean pain score in two groups. The minimum pain score among patients was 1 and maximum was 4 with mean and standard deviation 2.95 ± 1.01. There was a significant difference found between pain score and groups i.e. Group 1 (Ledermix paste), Group 2 (Calcium hydroxide) with p-value < 0.001. Both Ledermix and Calcium hydroxide reduces the inter appointment pain in patients but Ledermix paste is more effective in pain control. Recommendation for the intracanal medicament i.e. Ledermix should be used in routine endodontic therapy.