Introduction. Due to being hard to heal, chronic ulcers account for high morbidity. Objective. This study compares the safety and efficacy of 2 formulations of cadexomer iodine and standard care for the treatment of chronic ulcers. Materials and Methods. This prospective, randomized, open-label clinical trial was conducted at 8 cities across 15 institutions in India from March 2016 to March 2017. After screening a total of 145 patients with chronic, recalcitrant ulcers, 124 were randomized to 1 of 3 treatments: 0.9% cadexomer iodine ointment plus standard care (n = 41), 0.9% cadexomer iodine powder plus standard care (n = 43), and standard care alone (n = 40). All patients completed the maximum treatment period of 12 weeks, with the exception of 8 who discontinued during the study period. At the end of the treatment period, endpoints were assessed. Results. The percentage of reduction in ulcer size from baseline to the primary endpoint of 12 weeks was significantly (P < .001) higher with both formulations of cadexomer iodine ointment (94.3% ± 10.6%) and powder (90.4% ± 14.9%) as compared with standard care alone (67.8% ± 21.8%). The percentage of patients with complete wound healing at the end of the 12 weeks was significantly (P < .01) higher in patients treated with both formulations of cadexomer iodine ointment (65.8%) and powder (58.1%) as compared with standard care alone (20.0%). Conclusions. These results demonstrate that cadexomer iodine, in comparison with standard care alone, increases the percentage of reduction in ulcer size and promotes complete wound healing in chronic ulcers.