Abstract: Background: This study evaluated clinical and economic outcomes associated with antiretroviral therapy (ART) resistance among people with HIV (PWH) within a nationally representative database. Methods: Retrospective claims data were extracted from the Veterans Affairs Informatics and Computing Infrastructure. PWH receiving testing for resistance-associated mutations (RAMs) between 2003 and 2023 were categorized as resistant if they had ≥1 documented RAM in integrase strand transfer inhibitor, protease inhibitor, or reverse transcriptase genes. Results: Among 7746 veterans with interpretable resistance tests, 1875 had no detectable resistance, 4466 had ≥1 major or minor RAM (any RAM), and 1405 had ≥1 major RAM. The median CD4 count was highest for those without RAMs (357 cells/mm3) and lowest for those with major RAMs (285 cells/mm3). Opportunistic infections during the 1-year follow-up were present in 3.8% without RAMs as compared with >5% for both RAM groups. Hospitalizations were more frequent in the major RAM and any RAM cohorts vs the no resistance cohort (P < .001 for both). Total all-cause costs averaged $45 476 for those without RAMs as compared with $49 945 for those with any RAM and $48 392 for those with a major RAM. Among PWH initiating ART after resistance testing (n = 3522), those without RAMs had the longest persistence, while those with RAMs had shorter persistence (P < .0001). PWH prescribed ART at the time of resistance testing who had RAMs were most likely to switch to a regimen based on an integrase strand transfer inhibitor or protease inhibitor. Conclusions: In this real-world analysis, PWH with detectable resistance had lower CD4 counts, more frequent hospitalizations and opportunistic infections, greater economic costs, and increased discontinuation of ART.