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Objectives Olfactory dysfunction is a relatively frequent manifestation in Systemic Lupus Erythematosus (SLE). This study aimed to evaluate the prevalence of smell impairment in SLE patients and its correlation with clinical and serological features, damage indices and imaging-detected microstructural alterations.Methods Forty patients fulfilling the 2019 EULAR/ACR classification criteria for SLE were enrolled. Clinical history, disease indices, and main laboratory parameters were collected and analyzed. Olfactory function was assessed using the Italian Olfactory Identification Test (IOIT). A subgroup of 20 patients underwent brain MRI with DTI and tractography of the olfactory tract, performed on a 3T clinical MRI scanner. Preprocessing was performed with DTIPrep; DTI reconstruction and fiber tracking were conducted using Diffusion Toolkit, and tractography analysis with TrackVis. Parameters extracted included fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD), and tract volume. Data were compared with 20 age- and sex-matched healthy controls. IOIT scores were analyzed in relation to clinical and imaging findings.Results The cohort included 40 patients (mean age±SD: 52.2 ± 13.9 years; disease duration: 20.9 ± 13.8 years; female/male ratio: 4:1). Hyposmia was observed in 32.5% of cases. IOIT scores correlated significantly with cumulative organ damage measured by SDI/SLICC (r=0.268, P<0.001). Moreover, hyposmia was strongly associated with anti-beta2GPI antibodies (P<0.01), which emerged as the main risk factor for smell dysfunction (OR=16.25, 95% CI 1.65-160.24). MRI analysis was feasible in 8 of the 20 MRI-scanned SLE patients. Compared with controls, SLE patients showed a significant reduction in olfactory tract volume (p=0.007), along with increased FA, MD, RD, and AD values, consistent with microstructural alterations.Abstract PO:12:325 Figure 1–2Abstract PO:12:325 Table 1–2Conclusions The IOIT is a suitable tool for evaluating olfactory dysfunction in SLE. The significant association between hyposmia and cumulative damage suggests that olfactory impairment may serve as a clinical marker of long-term organ damage. Furthermore, anti-phospholipid antibodies, particularly anti-beta2GPI, appear to predict the development of hyposmia, reinforcing the link between olfactory dysfunction and chronic damage in SLE. Additionally, DTI and tractography findings support a central, possibly ischemic or inflammatory, origin of olfactory impairment.