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Background: Longitudinal studies assessing depression and anxiety effects on cognition in multiple sclerosis (MS) are limited. Objective: We tested whether within-person fluctuations in symptoms of depression or anxiety over time affect cognition in persons with MS, inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and a lifetime history of depression/anxiety disorders (DEP/ANX) but without an immune-mediated inflammatory diseases (IMID). Methods: We followed participants (MS: 255, IBD: 247, RA: 154, and DEP/ANX: 306) for 3 years. Annually, they completed the hospital anxiety and depression scale (HADS) and cognitive tests including the symbol digit modalities test (SDMT). We evaluated associations of elevated symptoms (scores > 11) of anxiety (HADS-A) and depression (HADS-D) with SDMTz-scores using multivariable linear models-estimating between-person and within-person effects. Results: Participants with MS performed worse on the SDMT than participants in the DEP/ANX cohort (beta = -0.68; 95% CI: -0.88, -0.48). Participants with elevated HADS-A scores performed worse on the SDMT than those without elevated scores (beta = -0.43; 95% CI: -0.65, -0.21), particularly those with RA. Time-varying within-person elevations in depressive symptoms were associated with worse SDMT performance (beta = -0.12; 95% CI: -0.21, -0.021). Conclusions: Across persons, elevated symptoms of anxiety adversely affected information processing. Elevated symptoms of depression within-persons over time were associated with declines in information processing speed.