BACKGROUND: Young men who have sex with men have a high HIV incidence, and a substantial proportion of incident infections occur in the context of main partnerships. However, romantic relationships also provide numerous benefits to individual health and wellbeing. 2GETHER is a relationship education and HIV prevention program for young male couples, and the 2GETHER USA randomized controlled trial (RCT) was launched to establish the efficacy of an online version of 2GETHER. OBJECTIVE: The objective of 2GETHER is to optimize relationship functioning in young male couples as a method to improve communication about sexual risk behaviors and reduce HIV transmission. In the 2GETHER USA study, 2GETHER was adapted for online administration to couples across the United States via videoconferencing. The intervention in question aims to address the unique needs of couples from varied racial/ethnic backgrounds and geographic regions. METHODS: This is a comparative effectiveness RCT of 2GETHER USA relative to existing public health practice (control). 2GETHER USA is a hybrid group- and individual-level intervention that delivers three weekly online group discussion sessions for skills delivery, followed by two individualized couple sessions that focus on skills implementation in each couple. The control condition differs by participant HIV status: (1) the Testing Together protocol for concordant HIV-negative couples; (2) medication adherence and risk reduction counseling for concordant HIV-positive couples; or (3) both protocols for serodiscordant couples. Follow-up assessments are delivered at 3-, 6-, 9-, and 12-months post-intervention in both conditions. Testing for rectal and urethral Chlamydia and Gonorrhea occurs at baseline and 12-month follow-up. The primary behavioral outcome is condomless anal sex with serodiscordant serious partners or any casual partners. The primary biomedical outcome is sexually transmitted infection incidence at a 12-month follow-up. RESULTS: As of October 11, 2019, the trial has enrolled and randomized 140 dyads (Individual N=280). Enrollment will continue until we randomize 200 dyads (N=400). Assessment of intervention outcomes at 3-, 6-, 9-, and 12-months is ongoing. CONCLUSIONS: 2GETHER is innovative in that it integrates relationship education and HIV prevention for optimizing the health and wellbeing of young male couples. The 2GETHER USA online adaptation has the potential to reach couples across the United States and reduce barriers to accessing health care services that are affirming of sexual minority identities for those who live in rural or under-resourced areas. TRIAL REGISTRATION: ClinicalTrials.gov NCT03284541; https://clinicaltrials.gov/ct2/show/NCT03284541. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/15883.