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Background and purpose: To analyze the relationship between cognitive processing speed, patient‐reported outcome measures (PROMs), employment and magnetic resonance imaging (MRI) metrics in a large multiple sclerosis cohort. Methods: Cross‐sectional clinical data, PROMs, employment and MRI studies within 90 days of completion of the Processing Speed Test (PST), a technology‐enabled adaptation of the Symbol Digit Modalities Test, were collected. MRI was analyzed using semi‐automated methods. Correlations of PST score with PROMs and MRI metrics were examined using Spearman's rho. Wilcoxon rank sum testing compared MRI metrics across PST score quartiles and linear regression models identified predictors of PST performance. Effects of employment and depression were also investigated. Results: In 721 patients (mean age 47.6 ± 11.4 years), PST scores were significantly correlated with all MRI metrics, including cord atrophy and deep gray matter volumes. Linear regression demonstrated self‐reported physical disability, cognitive function, fatigue and social domains (adjusted R2 = 0.44, P < 0.001) as the strongest clinical predictors of PST score, whereas that of MRI variables included T2 lesion volume, whole‐brain fraction and cord atrophy (adjusted R2 = 0.42, P < 0.001). An inclusive model identified T2 lesion volume, whole‐brain fraction, self‐reported upper extremity function, cognition and social participation as the strongest predictors of PST score (adjusted R2 = 0.51, P < 0.001). There was significant effect modification by depression on the relationship between self‐reported cognition and PST performance. Employment status was associated with PST scores independent of age and physical disability. Conclusion: The PST score correlates with PROMs, MRI measures of focal and diffuse brain injury, and employment. The PST score is a feasible and meaningful measure for routine multiple sclerosis care. [ABSTRACT FROM AUTHOR]