Loneliness is a common health problem among the elderly but is not well understood in the adolescent population, especially in low- and middle-income countries (LMICs). Adolescent loneliness can have adverse impacts on short- and long-term health status. This study examined rates of self-reported loneliness and friendlessness among 76,982 secondary school students in 25 LMICs in Latin America and the Caribbean who participated in the Global School-based Student Health Survey (GSHS). After calculating the rates of reported loneliness and lack of close friends separately for nationally representative samples of boys and girls from each country, we used meta-analysis to pool results for prevalence rates and associations across all 25 countries and territories. About 1 in 6 students (18.1% [95% CI: 16.4%, 20.0%]) reported being lonely most or all of the time and/or having no close friends, including 19.9% of girls and 16.2% of boys. Girls were more likely than boys to report being lonely most or all of the time (14.6% vs. 9.2%, p < .05), but boys were more likely than girls to report that they had zero close friends (8.7% vs. 7.2%, p < .05). However, the majority of students who reported being lonely did not report having no close friends, and the majority of students who reported having no close friends did not report being lonely most or all of the time. Asking adolescents about both loneliness and friendships may capture the burden of social isolation among males and females better than a single question about loneliness. Successful interventions for reducing social isolation must be rooted in communities and integrated into comprehensive school and community health plans. © 2019 Association for Child and Adolescent Mental Health.