Background: Human papillomavirus (HPV) is one of the most significant risk factors for cervical cancer. The HPV vaccine has a very significant impact on the incidence of cervical cancer. The present study aimed to investigate the impact of prophylactic quadrivalent HPV vaccine in the treatment of women with cervical intraepithelial neoplasia (CIN 1-3). Methods: This randomized controlled trial was conducted in the Shahid Sadoughi University of Medical Sciences (SSUMS), Yazd, Iran, from October 2011 to November 2015 in women with histologically confirmed residual/ recurrent CIN 1 or high-grade CIN (CIN 2-3). Eligible women were assigned randomly to an intervention and a control group. Women in the intervention group were given HPV vaccinations while those in the control group were not. Participants were followed up for 24 months. Primary and secondary outcomes, and adverse effects of the treatment in the two groups were compared using Student's t test, the chi-square test, or Fisher's exact test. P values < 0.05 or less were considered statistically significant. Results: Three-hundred and twelve women were randomized to the two groups; the data of 138 in the intervention group and 104 in the control group were analyzed. The mean age of the women was 32.59 ± 4.85 years. Differences in age, marital status, and grades of CIN weren't significant between the two groups. At the end of the two-year follow-up period, the number of women with CIN 2-3 in the intervention and control groups was reduced by 75% (from 93 to 23) versus 40% (from 69 to 41). The efficacy of the HPV vaccine in women with CIN 1-3 was 58.7% (p = 0.018). No serious adverse effects related to the vaccines were reported. Conclusions: The prophylactic quadrivalent HPV vaccine after treatment may have a therapeutic effect in women with residual/recurrent CIN 1 or high-grade CIN (CIN 2-3). Trial registration: Iranian Registry of Clinical Trials, IRCT20190603043801N1.