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Objectives Cognitive impairment (CI) is common in people with systemic lupus erythematosus (pwSLE) and negatively impacts quality of life. The underlying neural mechanisms remain unclear, with structural MRI showing inconsistent associations with CI. Functional MRI (fMRI) has demonstrated stronger associations. This study aimed to identify functional brain differences between pwSLE and healthy controls (HC) during cognitive processing and to explore compensatory mechanisms supporting cognition in SLE.Methods SLE participants meeting EULAR/ACR classification criteria and HC were recruited. MRI acquisition included structural and task-based fMRI during two stages of a cognitive task assessing attention, working memory (WM), learning, and associative memory. Stage 1 examined encoding, WM, and retention; Stage 2 assessed long-term retrieval ( figure 1). Group differences in performance were analysed with t-tests. fMRI data were modelled in SPM12 to compare blood-oxygen-level-dependent (BOLD) responses between groups (cluster-level family-wise error corrected, pFWEc < 0.05; cluster threshold p = 0.0005).Results 40 pwSLE and 18 HC were recruited. After preprocessing, data from 34 pwSLE and 17 HC were eligible for analysis. Mean ages were 41 (11 SD) and 42 (14 SD) years; females comprised 80% and 50%, and university graduates 43% and 100%, for pwSLE and HC respectively. For pwSLE, mean disease duration was 15 (10 SD) years, SLEDAI-2K score was 3 (4 SD), and antimalarial, corticosteroid, and immunosuppressant use was 78%, 45%, and 65%, respectively. Behavioural task performance did not differ between groups. During encoding, HC had greater BOLD responses than pwSLE across frontal, motor, cerebellar, and temporal regions ( figure 1, table 1). No differences were seen in retention. In the WM phase, pwSLE showed increased BOLD response in the right middle frontal gyrus. During retrieval, HC had a greater BOLD response near the right lateral ventricle, while pwSLE had greater responses in the left posterior insula (table 1).Abstract S3:04 Figure 1–2Abstract S3:04 Table 1BOLD responses from the cognitive task, split by stage and component, that had significant differences (pFWEc < 0.05) between the pwSLE and HC groupsConclusions pwSLE exhibited altered BOLD responses compared to HC during cognitive processing. HC recruited typical attention, WM, and visuospatial regions more efficiently, while pwSLE showed reduced engagement and compensatory responses particularly in the right middle frontal gyrus. Distinct retrieval patterns suggest alternative neural strategies, supporting functional reorganisation that may preserve cognition despite neural inefficiency.