Abstract Background Peyronie’s disease (PD), defined as the abnormal formation of fibrous plaque(s) in the tunica albuginea of the penis, is a chronic condition that afflicts 3% to 13% of the US male population; there is no current research on the efficacy and safety of collagenase Clostridium histolyticum (CCH) in the treatment of acute phase PD. Aim To examine the efficacy and safety of CCH in the treatment of acute-phase PD. Methods We retrospectively reviewed the records for all patients treated with CCH for PD from April 2014 through April 2017. Patients who reported penile pain and duration of PD no longer than 12 months at presentation qualified as being in the acute phase of PD. The primary outcomes of interest were final changes in curvature after CCH treatment regardless of the number of CCH cycles received and frequency of treatment-related adverse events. Outcomes Parameters of efficacy and safety were compared between acute- and stable-phase PD. Results A total of 162 patients were included in the study, of which 36 (22%) qualified as having acute-phase PD (group 1) and the remaining 126 (78%) qualified as having stable-phase PD (group 2). Median duration of PD was 8.5 months (range = 1–12) for group 1 and 18 months (range = 1–492) for group 2. There was no significant difference in final change in curvature between the acute and stable phases of PD (16.7° vs 15.6°; P = .654). There was no statistically significant difference in frequency of treatment-related adverse events between the acute phase (4 patients, 11%) and the stable phase (12 patients, 10%; P = .778). Clinical Implications CCH therapy is as safe and efficacious in acute-phase PD as it is in stable-phase PD. Strengths and Limitations This is the first report that assesses the safety and efficacy of CCH therapy focusing on acute-phase PD. This study was composed of a large cohort of patients receiving CCH therapy in acute- and stable-phase PD. Limitations include bias associated with retrospective studies, a small sample, and a single-center setting. Conclusions Although CCH is not clearly indicated for treatment during the acute phase of PD, these results suggest that CCH use during this phase can be effective and safe. There was no statistically significant difference in final change in curvature or treatment-related adverse events after CCH therapy delivered between the acute and stable phases of PD.