Purpose: To compare the efficacy and safety of intralesional hyaluronic acid (HA) as compared with verapamil injection in patients with Peyronie's disease (PD). Materials and Methods: Between January 2015 and December 2018, men in PD acute phase were prospectively recruited. This open-label, prospective study included 2 different protocols. Group A: 8-week cycle of weekly intraplaque injections with HA; Group B: 8-week cycle of weekly intraplaque injections with verapamil. Penile curvature, plaque size, International Index of Erectile Function (IIEF)-15 score and visual analogue scale (VAS) were assessed at baseline and after 3 months. Results: Two-hundred forty-four patients were enrolled. Of these, 125 received intralesional HA (Group A), 119 received intralesional verapamil (Group B). At enrollment, median age was 56.0 years (interquartile range [IQR]=47.0-63.0 years), median curvature 35.0° (IQR=25.0°-45.0°), median IIEF-15 score 19.0 (IQR=16.0-23.0), median VAS 4.0 (IQR=4.0-5.0). Median difference for IIEF-15 was 1.0 (95% confidence interval [CI]=1.12-1.94) in Group A and 0.0 (95% CI=-0.04-0.14) in Group B (p<0.05) and median difference for VAS score was-4.0 (95% CI=-4.11-3.65) in Group A and-1.0 (95% CI=-0.50-2.01) in Group B (p<0.05). Plaque size decreased by-1.50 mm (IQR=1.60-2.10 mm) in Group A and-1.20 in Group B (p=0.10), while penile curvature decreased by-9.50° (IQR=4.50°-13.00°) in group A and-4.50 (IQR=2.50-7.50) in Group B (p<0.01). Conclusions: Intralesional HA injections could represent a reliable treatment option for the conservative management of patients with acute phase of PD.