Background. While use of some older antiretroviral drugs (ARVs) is associated with chronic liver enzyme elevation (cLEE), the impact of newer ARVs remains unknown. Methods. People with HIV enrolled in the RESPOND cohort who started an ARV after January 1, 2012 were included (baseline). The primary outcome was first cLEE individuals were censored at first of cLEE, last visit, death, or December 31, 2021. Incidence rates (IRs; events/1000 person-years) were calculated for each ARV overall and by ARV exposure (6–12 months, 1–2 years, and 2+ years). Poisson regression was used to estimate the incidence rate ratio (IRR) of cLEE and its association with individual ARVs and ARV class. Results. Of 17 106 individuals included contributing 87 924 person-years of follow-up, 1932 (11.3%) experienced cLEE (incidence rate [IR], 22.0; 95% CI, 21.0–23.0). There was no evidence of a cumulative ARV effect on cLEE incidence, (6–12 months: IR, 45.8; 95% CI, 41.4–50.19; 1–2 years: IR, 34.3; 95% CI, 31.5–37.4; and 2+ years: IR, 18.5; 95% CI, 17.4–19.7). Any use (vs no prior use) of non-nucleoside reverse transcriptase inhibitors (NNRTIs) as a class and tenofovir disoproxil fumarate (TDF) was independently associated with an increased IRR of cLEE, and any use of darunavir (DRV) was associated with a decreased risk of cLEE. Conclusions. cLEE is common and more frequent during the first year after initiating new ARVs. With a >5-year median follow-up, we found no short-term liver safety concerns with the use of INSTIs. Use of NNRTIs and TDF was associated with an increased cLEE risk, while DRV was associated with lower risk.