We conducted a systematic review of couple-based HIV biobehavioral (skills-building, VCT, and adherence) and biomedical (ART, circumcision) prevention and intervention studies designed to reduce sexual-and drug-risk behaviors and HIV transmission and acquisition. Of the 11,162 papers identified in the search, 93 peer-reviewed papers met the inclusion criteria and yielded a total of 33 studies conducted globally. Biobehavioral couple-based prevention and intervention studies have been efficacious in reducing sexual- and drug-risk behaviors, increasing access to HIV testing and care, and improving adherence. Biomedical couple-based studies were found to reduce HIV incidence among HIV-negative sex partners and viral load among HIV-positive partners. Despite much progress, couple-based HIV prevention and intervention studies remain limited; a number of methodological gaps exist and studies focusing on MSM, people who inject drugs, and sex workers are scarce.