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Cognitive impairment varies widely in bipolar disorder. Identifying cognitive subgroups and their biological correlates may improve understanding of the disorder. Brain-derived neurotrophic factor (BDNF) and C-reactive protein (CRP) are key candidates due to their roles in neuroplasticity and inflammation. The aim was to investigate cognitive subgroups in patients with bipolar disorder and their association with serum levels of BDNF and CRP. A cross-sectional study was conducted on 149 bipolar disorder patients and 48 healthy controls. Cognitive performance was assessed using a comprehensive battery of neuropsychological tests. Cluster analysis was performed to identify cognitive subgroups, followed by discriminant function analysis to validate the classification. Serum levels of BDNF and CRP were measured and compared across cognitive subgroups. Cluster analysis identified three cognitive subgroups: intact cognition, selectively impaired cognition (SIC) and globally impaired cognition (GIC). SIC exhibited the highest BDNF levels, while GIC demonstrated the highest CRP levels. CRP levels were negatively associated with performance across all cognitive domains. BDNF showed a negative correlation with verbal fluency, short-term memory and working memory. CRP levels exceeding 4.3 mg/L predicted global cognitive impairment with a sensitivity of 72.41% and specificity of 73.63%. Cognitive impairments in bipolar disorder patients can be classified into distinct subgroups, which are associated with serum levels of BDNF and CRP. These findings suggest that inflammation and neuroplasticity play key roles in the pathophysiology of cognitive decline in bipolar disorder, providing potential biomarkers for identifying patients at risk for severe cognitive impairments. Show less