Objective To report on an early adopter series of collagenase Clostridium histolyticum (CCh) for Peyronie's disease (PD). Postapproval studies of CCh have been anticipated after recent Food and Drug Administration authorization of its use for men with PD as definitive and durable nonsurgical interventions have been long desired. Materials and Methods From May 2014 to October 2015, a database consisting of PD patients with >30° of penile curvature received CCh from a single provider at a single institution. Objective penile curvature measurements and deformity directions were assessed pre- and posttreatment. Using the validated Peyronie's Disease Questionnaire (PDQ), changes in subjective symptoms of intercourse ability, penile pain, and bother were also noted. Results We followed 49 unique PD patients treated with CCh. Mean follow-up was 183 days with a median of 6 injections over 3 cycles performed per patient. The mean pretreatment penile curvature was 49.3 degrees. Curvature was reduced by 15.4 degrees (32.4%, P  < .01) after therapy. There were 10 out of 22 patients who regained ability to perform vaginal intercourse. Subjectively, there was an improvement in the ability to perform intercourse (29.1% improvement, P  < .01) and bother symptoms (mean decrease 43.2%, P  < .01), but no significant changes in penile pain ( P  = .89). Five notable bleeding events (10.2%) were noted, including 1 penile fracture requiring operative exploration. Conclusion CCh use for PD yielded improvements in penile curvature, subjective intercourse, and bother symptoms. Further postanalysis studies of greater follow-up are needed to assess long-term durability, efficacy, and safety.