Research is lacking on factors associated with antiretroviral therapy (ART) sub-optimal adherence among U.S. Latinos, who are disproportionately affected by HIV and face substantial health care barriers. We examined self-reported, patient-initiated changes to ART (i.e., made small/major changes from the antiretroviral drugs prescribed) among HIV-positive Latinos. Trained interviewers administered surveys to 230 participants currently on ART in San Diego, U.S. and Tijuana, Mexico. We identified factors independently associated with ART changes. Participants were Spanish-language dominant (86%), mean age of 41 years, male (77%), and born in Mexico (93%). Patient-initiated changes to ART were reported in 43% of participants. Being female, having ≥1 sexual partner (past 3 months), ≤6 years since HIV diagnosis and poor health were associated with increased odds of ART changes. Findings raise concern about sub-optimal adherence among this binational population. Longitudinal studies are needed to further explore adherence barriers and avenues for intervention.