The purpose of this study was to investigate the effect of two-step irradiance schedule in relieving pain during PDT of CA. The study was a prospective, controlled trial of 141 CA patients who were randomly divided into Group A (two-step irradiance schedule) and Group B (single-dose cold compress). The numeric rating scales (NRS) of patients' pain were recorded at 5, 10, 15, and 20 minutes during each PDT. The efficacy of PDT and NRS scores of patients in the two groups were compared. There was no significant difference in gender, age, lesion site, and disease course between the two groups (P > 0.05). In addition, the cure rate of patients in the two groups was not significantly different (97.1% vs. 95.8%, χ2  = 0.000, P = 1.000). However, the NRS scores at different time points and number of PDT sessions were significantly different (F = 198.233 and 165.224, respectively, P < 0.05). The NRS scores of patients in Group A were significantly lower than those of patients in Group B (F = 82.762, P < 0.0001). Moreover, the NRS scores at different positions were significantly different (F = 28.286, P < 0.0001). The NRS scores of penis were significantly lower than those of the vulva and crissum (P < 0.05). Compared with single-dose cold compress, two-step irradiance schedule could more significantly reduce the patients' pain degree during treatment, especially for vulva and crissum. Lasers Surg. Med. 49:908-912, 2017. © 2017 Wiley Periodicals, Inc.