Introduction and Aims. Past research investigating syndemic factors and HIV-related outcomes has overlooked the impact of structural conditions on behaviours linked with HIV transmission and disease progression. Given prevalent substance use among our sample, we explored whether four structural conditions indicative of social marginalisation and previously correlated with increased risk for HIV infection demonstrated syndemic (additive/synergistic) effects on: (i) HIV viral suppression; and (ii) self-reported involvement in sexual HIV transmission behaviours among a prospective cohort mostly comprising men of colour who have sex with men (MCSM; i.e. Latino/Hispanic and African American/black men) in Los Angeles County. Design and Methods. Data were collected between August 2014 and March 2017. The structural conditions of interest were: current unemployment, recent (≤6 months) incarceration history, 'unstable' accommodation (past month) and remote (>6 months) contact with health-care providers. Generalised estimating equations assessed possible additive effects of experiencing multiple structural conditions, and possible synergistic effects on the HIVrelated outcomes. Results. Of 428 participants, nearly half (49%) were HIV-positive at baseline. Involvement in sexual HIV transmission risk behaviours varied over follow-up (22-30%). Reporting ≥2 structural syndemic conditions was significantly associated with reporting sexual HIV transmission risk behaviours among HIV-negative participants, and detectable viral load among HIV-positive participants. Frequent methamphetamine use was consistently associated with the HIV-related outcomes across the final multivariate models. Discussion and Conclusions. When developing initiatives to address HIV transmission among marginalised sub-populations including MCSM, we must holistically consider systemic and structural issues (e.g. unemployment and homelessness), especially in the context of prevalent substance use. [Quinn B, Gorbach PM, Okafor CN, Heinzerling KG, Shoptaw S. Investigating possible syndemic relationships between structural and drug use factors, sexual HIV transmission and viral load among men of colour who have sex with men in Los Angeles County. Drug Alcohol Rev 2020;39:116-127]