This study details virologic and resistance outcomes in the combined population of ODYSSEY participants, namely children starting first-line ART (ODYSSEY A) and second-line therapy after treatment failure (ODYSSEY B). Data were available for 788 participants: 189 in the dolutegravir ODYSSEY A group vs. 192 receiving standard of care (SOC), and 202 in the dolutegravir ODYSSEY B group vs. 205 receiving SOC. Median prior ART exposure in ODYSSEY B was 5.3 years, with 96% previously on NNRTI-based regimens. NRTI backbones were balanced across groups: ABC/3TC was most commonly used, followed by TDF/XTC, then ZDV/3TC. Overall, 51/391 (13%) had virologic failure by 96 weeks in the dolutegravir group vs. 86/397 (22%) receiving SOC (p=0.0011). Baseline resistance tests were available for 71% of ODYSSEY B participants, with 92% having high-level resistance to XTC, 29% to ABC, 4% to TDF, and 2% to ZDV. Among ODYSSEY B participants receiving dolutegravir, failure was higher in children starting ZDV (HR 2.22, p=0.048). Of the total 137 participants with failure by week 96, resistance testing after failure was available for RT and PR in 133/137 and for INI in 42/51 receiving dolutegravir. None of the participants receiving first-line dolutegravir had emergent major INSTI resistance. Five participants receiving second-line dolutegravir had at least one major INSTI mutation after failure (Q148Q/R, Q148K, N155N/H, G118R/S, G118G/R/S+R263R/K—all with cabotegravir cross-resistance).