Objective The purpose of this in vivo study was to evaluate pain using different intracanal medicaments. Materials and Methods Seventy-five permanent single-rooted mandibular premolars with acute apical periodontitis were selected for this study. After access cavity preparation and cleaning and shaping of canals, patients were randomly divided into five groups with different intracanal medicaments viz calcium hydroxide paste, calcium hydroxide points, triple antibiotic paste, and Ledermix paste. Interappointment pain was recorded by the patient using visual analog scale after 6 hours, 12 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, and 6 days of intracanal medicament dressing. Results Ledermix paste showed highly significant results in reducing the interappointment pain as compared with calcium hydroxide paste, calcium hydroxide points, and triple antibiotic paste. Conclusion Patients with Ledermix as intracanal medicament had minimum interappointment pain.