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Background Statins are proven to reduce cardiovascular risk in people with HIV (PWH), but the comparative impact of hydrophilic versus lipophilic statins on metabolic complications remains uncertain. The primary objective of this study was to compare longitudinal changes in Homeostatic Model Assessment for insulin resistance (HOMA-IR) among PWH treated with rosuvastatin vs. atorvastatin. The secondary objectives were to evaluate baseline HOMA-IR in participants without IR and to determine the incidence of new-onset IR and diabetes mellitus among PWH.Methods This was a longitudinal observational study including PWH ≥ 40 years attending Modena HIV Metabolic Clinic, Italy, from 2004 to 2024 who initiated atorvastatin or rosuvastatin and had available HOMA-IR within ±6 months of initiation. PWH with pre-existing DM, missing HOMA-IR, or use of statins other than atorvastatin or rosuvastatin were excluded. Insulin resistance (IR) was defined as HOMA-IR ≥2.5. Baseline was defined as the earliest statin initiation with complete available data, while follow-up as time from statin initiation to IR, DM onset, or last available visit. Linear mixed models (LMMs) were used to compare HOMA-IR trends overall and among those without baseline IR.Results We included 627 PWH (median age 55, 76% male, median CD4: 673 cells/microL, median time since HIV diagnosis 22 years, median HOMA-IR: 2.5, 48% with baseline IR. Atorvastatin was started in 235 and rosuvastatin in 285 patients, with 62 and 45 crossovers, respectively, during a median follow-up of 1.9 years. No major baseline differences were observed. During follow-up, 96 patients developed IR with no significant difference between treatments (13.9 vs 14.3 per 100 PY; p=0.92; IRR=1.03) ( figure 1) and 10 developed DM (1.03 vs 1.04 per 100 PY; p=0.88). In unadjusted and adjusted LMM, statin use was not associated with higher overall HOMA-IR (figure 2) or higher HOMA-IR in those without baseline IR (figure 3). Similarly, adjusted LMM showed no significant differences between the two statins in overall HOMA-IR or among PWH without baseline IR (table 1).Conclusions Rosuvastatin and atorvastatin showed comparable effects on HOMA-IR trajectories and on the risk of new-onset IR or diabetes. The modest increase in insulin resistance over time appears more related to underlying metabolic status and HIV-associated risk factors than to the specific statin used. These findings support the overall metabolic safety of both statins in PWH and provide reassurance for their use in cardiovascular risk management.Abstract OC46 Figure 1–3 and Table 1