Our objectives were to describe trends in enrolment and clinical outcomes in the open, prospective Kilombero and Ulanga Antiretroviral Cohort (KIULARCO) in the Morogoro region of southern Tanzania, and identify strengths and areas for improvement in the care of HIV-positive individuals in rural Tanzania.We included adults (≥15 years) and children (<15 years) enrolled in the cohort in 2005-2014. The cohort underwent significant changes from autumn 2012 to optimise care. We evaluated mortality and loss to follow-up (LTFU) using competing risks methods, ART usage, opportunistic infections (OI), co-infections and laboratory abnormalities.Overall, 7010 adults and 680 children were enrolled; enrolment peaked in 2008 but has increased steadily since 2011. Among adults (65% female; median age 37 [interquartile range 31-45] years), the proportion referred from hospital wards quadrupled in 2013-14 versus earlier years. 653 (9%) adults died and 2648 (38%) were LTFU; the five-year cumulative probabilities of death and LTFU were 10.3% and 44.0%, respectively. Among children, 69 (10%) died and 225 (33%) were LTFU. The corresponding five-year probabilities were 12.1% and 39.6%. Adult ART use (regardless of eligibility) increased from 5% in 2005 to 89% in 2014 (similarly among children), with 9% on second-line therapy in 2014 (17% of children). OI diagnoses increased over time; tuberculosis prevalence at enrolment quadrupled from 6% in 2011 to 26% in 2014. The proportion of newly-enrolled participants assessed for laboratory abnormalities peaked at nearly 100% in 2014 (from a minimum of 24%), yet abnormality prevalences remained fairly constant.In this cohort, ART usage improved dramatically and is approaching targets of 90%. Improved screening led to increases in detection of OIs and laboratory abnormalities, suggesting that a large number of these co-morbidities previously went undetected and untreated. Further work will address the high LTFU rates and implications for mortality estimates, and the management and outcomes of co-morbidities.