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Objective: Untreated mental disorders are important among low- and middle-income country (LMIC) university students in Latin America, where barriers to treatment are high. Scalable interventions are needed. This study compared transdiagnostic self-guided and guided internet-delivered cognitive behavioral therapy (i-CBT) with treatment as usual (TAU) for clinically significant anxiety and depression among undergraduates in Colombia and Mexico. Method: 1,319 anxious, as determined by the Generalized Anxiety Disorder–7 (GAD-7) = 10+ and/or depressed, as determined by the Patient Health Questionnaire–9 (PHQ-9) = 10+, undergraduates (mean [SD] age = 21.4 [3.2]); 78.7% female; 55.9% first-generation university student) from seven universities in Colombia and Mexico were randomized to culturally adapted versions of self-guided i-CBT (n = 439), guided i-CBT (n = 445), or treatment as usual (TAU; n = 435). All randomized participants were reassessed 3 months after randomization. The primary outcome was remission of both anxiety (GAD-7 = 0–4) and depression (PHQ-9 = 0–4). We hypothesized that remission would be higher with guided i-CBT than with the other interventions. Results: Intent-to-treat analysis found significantly higher adjusted (for university and loss to follow-up) remission rates (ARD) among participants randomized to guided i-CBT than either self-guided i-CBT (ARD = 13.1%, χ12 = 10.4, p =.001) or TAU (ARD = 11.2%, χ12 = 8.4, p =.004), but no significant difference between self-guided i-CBT and TAU (ARD = −1.9%, χ12 = 0.2, p =.63). Per-protocol sensitivity analyses and analyses of dimensional outcomes yielded similar results. Conclusions: Significant reductions in anxiety and depression among LMIC university students could be achieved with guided i-CBT, although further research is needed to determine which students would most likely benefit from this intervention. What is the public health significance of this article?: Anxiety and depression are significant public health problems in LMIC universities. A culturally adapted transdiagnostic-guided i-CBT could help alleviate these problems as a low-threshold intervention component of a stepped-care treatment delivery model. [ABSTRACT FROM AUTHOR]