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Objectives Hydroxychloroquine (HCQ) is a cornerstone therapy in systemic lupus erythematosus (SLE), as it reduces the risk of flares and improves pregnancy outcomes. Current guidelines therefore recommend HCQ use in all patients with SLE. Nevertheless, discontinuation may be required due to adverse events such as hypersensitivity reactions or retinopathy. We investigated the long-term retention rate of HCQ. In addition, since several studies have reported that desensitization protocols may allow successful reintroduction of HCQ in patients who failed standard induction, we also evaluated drug retention in this population.Methods We retrospectively analyzed patients with SLE followed at a tertiary referral center in Japan. Kaplan–Meier survival analysis was used to evaluate HCQ retention, and Cox proportional hazards models identified factors associated with discontinuation. We also assessed long-term outcomes in patients treated with a desensitization protocol.Results Of 447 patients screened, 365 (81.7%) received HCQ during their disease course. Among them, 357 initiated therapy at the standard dosage, while 8 commenced with desensitization. The retention rate for standard induction was approximately 90% at 52 weeks and 80% at 260 weeks. Older age at disease onset (>40 years) and chronic kidney disease (CKD) stage 4–5 were significantly associated with higher risk of discontinuation (age >40 years: HR 1.79, 95% CI 1.04–3.08, p=0.036; CKD stage 4–5: HR 5.09, 95% CI 1.85–14.14, p=0.0018). No associations were observed with immunological profiles, including anti-SSA antibody status.The HCQ desensitization protocol was applied in 26 patients, including 18 who had failed standard induction. After desensitization, 23/26 patients (88.5%) continued HCQ beyond 52 weeks. Long-term retention remained above 80% at 260 weeks, and no significant predictors of discontinuation were identified.Abstract PO:12:315 Figure 1Conclusions Long-term HCQ retention was approximately 80% after standard induction, with elderly-onset SLE and advanced CKD associated with poorer outcomes. Importantly, desensitization enabled successful reintroduction in nearly 90% of patients who had failed initial induction, with favorable long-term retention. These findings underscore the value of desensitization as an effective strategy to maintain HCQ therapy in patients otherwise intolerant to the drug.