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Objective To investigate the main and interactive effects of sex and disease diagnosis on cortical morphology in systemic lupus erythematosus (SLE), providing neuroimaging evidence for sex-by-disease interactive mechanisms underlying structural brain alterations.Methods A cross-sectional study design was used to recruit participants. Structural MRI scans were acquired and processed using surface-based morphometry (SBM) to extract cortical thickness (CT), gyrification index (GI), fractal dimension (FD) and sulcal depth (SD) within predefined regions of interest. Two-way analysis of variance assessed main effects and ‘sex×diagnosis’ interactions (Holm-Bonferroni corrected). Correlation analyses were performed between these structural metrics and SLE disease activity/psychological assessment scores in areas showing significant interactions.Results 196 individuals participated in this study: 30 male SLE patients, 66 female SLE patients, 33 male healthy controls (HC) and 67 female HC. Significant sex-by-disease interactions were detected: SD in left orbital (H-shaped) sulci (S_orbital-H_Shaped) ( F=14.8458, p=0.0150), with male HC >male SLE (p=0.0039) and male HC>female HC (p<0.0001), and GI in left middle frontal sulcus (S_front_middle) (F=14.1650, p=0.0313), with female SLE>male SLE (p<0.0001) and male HC>male SLE (p=0.0003). Diagnostic main effects (HC>SLE) were observed extensively for CT across both hemispheres. No significant correlations emerged between disease activity/psychological assessment scores and structural parameters in interaction-significant regions.Conclusion This study provides novel evidence for sex-by-diagnosis interactive effects in the neuropathological mechanisms of SLE. Sex and SLE disease status have both independent and interacting impacts on cerebral cortical structure.Trial registration number NCT00703742.