Engaging adolescent boys and young men in preventing violence against women is a potentially impactful public health strategy. To evaluate the effectiveness of a community-based, gender-transformative program (ie, Manhood 2.0) on perpetration of gender-based violence by adolescent boys and young men. In this unblinded cluster randomized clinical trial, neighborhoods were designated as the unit of clustering (1:1 allocation). Three-month (ie, time point 2 [T2]) and 9-month (ie, time point 3 [T3]) follow-ups were conducted. The trial took place in 20 Pittsburgh, Pennsylvania, neighborhoods and 1 centrally located site with concentrated disadvantage. Pittsburgh-based adolescent boys and young men (ages 13 to 19 years) were recruited between July 27, 2015, and June 5, 2017, through youth-serving organizations and community-based alternatives to residential placement for juvenile justice-involved youth. Intention-to-treat analysis was conducted from June 2018 to November 2019. Manhood 2.0, an international program adapted for adolescent boys and young men in US urban communities, encourages these individuals to challenge gender norms that foster violence against women and unhealthy sexual relationships. Individuals in the control population received job-readiness training. Each program was 18 hours. The primary outcome was change in participant-level perpetration of sexual violence (SV) or adolescent relationship abuse (ARA) at T3. Among 866 participants, 465 individuals (54%) enrolled in 11 intervention clusters and 401 individuals (46%) enrolled in 10 control clusters. In the intervention group, 325 participants (70%) were analyzed at T2 and 334 participants (72%) were analyzed at T3; in the control group, 262 participants (65%) were analyzed at T2 and 301 participants (75%) were analyzed at T3. Mean (SD) age was 15.5 (1.6) years; 609 participants (70%) self-identified as non-Hispanic Black, and 178 (20%) self-identified as Hispanic, multiracial, or other race/ethnicity other than White. Among individuals in the intervention group, 296 participants (64%) reported any SV or ARA perpetration at baseline, and 173 participants (52%) reported any SV or ARA perpetration at T3. Among individuals in the control group, 213 participants (53%) reported any SV or ARA perpetration at baseline, and 124 participants (41%) reported any SV or ARA perpetration at T3). The difference in reduction between groups was not significant. There was no evidence of an intervention effect for the primary outcome (adjusted odds ratio [OR], 1.32; 95% CI, 0.86-2.01; P = .20). The findings from this evaluation of a community-based gender-transformative program for adolescent boys and young men did not show a significant intervention effect in reducing SV or ARA perpetration between Manhood 2.0 and a job-readiness control program. Combining gender-transformative approaches with job-readiness programs may be relevant for violence prevention in low-resource urban settings. Attention to improving implementation and strategies to sustain such community-based efforts are needed. ClinicalTrials.gov Identifier: NCT02427061.