Background. Efavirenz (EFV) and boosted protease inhibitors (bPIs) are still the preferred options for firstline antiretroviral regimens (firstline ART) in Latin America and have comparable short-term efficacy. We assessed the long-term durability and outcomes of patients receiving EFV or bPIs as firstline ART in the Caribbean, Central and South America network for HIV epidemiology (CCASAnet). Methods. We included ART-naïve, HIV-positive adults on EFV or bPIs as firstline ART in CCASAnet between 2000 and 2016. We investigated the time from starting until ending firstline ART according to changes of third component for any reason, including toxicity and treatment failure, death, and/or loss to follow-up. Use of a third-line regimen was a secondary outcome. Kaplan-Meier estimators of composite end points were generated. Crude cumulative incidence of events and adjusted hazard ratios (aHRs) were estimated accounting for competing risk events. Results. We included 14 519 patients: 12 898 (89%) started EFV and 1621 (11%) bPIs. The adjusted median years on firstline ART were 4.6 (95% confidence interval [CI], 4.4-4.7) on EFV and 3.8 (95% CI, 3.8-4.0) on bPI (P < .001). Cumulative incidence of firstline ART ending at 10 years of follow-up was 32% (95% CI, 31-33) on EFV and 44% (95% CI, 39-48) on bPI (aHR, 0.88; 95% CI, 0.78-0.97). The cumulative incidence rates of third-line initiation in the bPI-based group were 6% (95% CI, 2.4-9.6) and 2% (95% CI, 1.4-2.2) among the EFV-based group (P < .01). Conclusions. Durability of firstline ART was longer with EFV than with bPIs. EFV-based regimens may continue to be the preferred firstline regimen for our region in the near future due to their high efficacy, relatively low toxicity (especially at lower doses), existence of generic formulations, and affordability for national programs.