There is an urgent need for efficient behavioral interventions to increase rates of HIV viral suppression for populations with serious barriers to engagement along the HIV care continuum. We carried out an optimization trial to test the effects of five behavioral intervention components designed to address barriers to HIV care continuum engagement for African American/Black and Latino persons living with HIV (PLWH) with non-suppressed HIV viral load levels: motivational interviewing sessions (MI), focused support groups (SG), peer mentorship (PM), pre-adherence skill building (SB), and navigation with two levels, short (NS) and long (NL). The primary outcome was HIV viral suppression (VS) and absolute viral load (VL) and health-related quality of life were secondary outcomes. Participants were 512 African American/Black and Latino PLWH poorly engaged in HIV care and with detectable HIV viral load levels in New York City, recruited mainly through peer referral. Overall, VS increased to 37%, or 45% in a sensitivity analysis. MI and SG seemed to have antagonistic effects on VS (z = - 1.90; p = 0.057); the probability of VS was highest when either MI or SG was assigned, but not both. MI (Mean Difference = 0.030; 95% CI 0.007-0.053; t(440) = 2.60; p = 0.010) and SB (Mean Difference = 0.030; 95% CI 0.007-0.053; t(439) = 2.54; p = 0.012) improved health-related quality of life. This is the first optimization trial in the field of HIV treatment. The study yields a number of insights into approaches to improve HIV viral suppression in PLWH with serious barriers to engagement along the HIV care continuum, including chronic poverty, and underscores challenges inherent in doing so.