Background: Globally antiretroviral therapy access has increased and significantly changed HIV morbidity and mortality patterns. In sub-Saharan Africa there are reports of increasing rates of failure to second-line antiretroviral treatment (ART) hence, assessment for clinical outcomes is critical. Objectives: To assess clinical outcomes and retention using programmatic indicators among HIV-infected adolescents and adults receiving second-line ART in Tanzania. Methods: In this longitudinal retrospective cohort study, we enrolled HIV-infected individuals aged 15 years and above who were initiated on second-line ART (Protease Inhibitor based regimen) due to documented failure of first-line ART between July 2012 and September 2015. We evaluated mean change in CD4 cell count, HIV viral load and retention using survival analysis. Results : A total of 1446 participants were enrolled, the mean duration of second-line therapy was 37.0 months± SD 26.50 and the median CD4 cell count at initiation of the second line was 290 cells/mm3. Virologic suppression <50 copies/ml was increasing over time and reached 58% at 36 months. Six months after switching, 80% of patients were retained and thereafter. Predictors of retention were male gender with hazard ratio (HR) 1.04; 95% CI 1.0-1.1 P-value 0.037 and younger age (25 -39 years) with HR 1.1; 95% CI 1.0-1.2 P-value 0.006. Additionally, adherence > 90% increased the likelihood of retention with a strong correlation HR 1.4; 95% CI 1.1-1.7 P-value 0.00. Clinical stage III and IV at switch were less likely to be retained HR 0.6; 95% CI 0.5-0.6 P-value 0.000 and higher CD4 cell count was associated with less retention HR <1; 95 % CI 0.4-0.6 P-value 0.000. Conclusion: There was a low rate of viral suppression (<50copies/ml) 58% 36 months after switch however, more than 87% of participants were retained to care after switch. Predictors of retention were male gender, younger age (25-39 years) and adherence > 90%. Therefore, improving viral suppression after switching to second-line requires further interventions.