Background Cognitive dysfunction is common among patients with multiple sclerosis (MS); however, the determinants of cognitive dysfunction are still unknown. This study aimed to investigate the determinants of cognitive dysfunction in a relatively large sample of patients with MS for rapid screening. Results Fifty-three patients (33.6%) had cognitive dysfunction. According to the Wechsler Memory Scale, patients with relapsing-remitting MS (RRMS) and patients with progressive MS (PMS) had significantly lower scores than the control group. Patients with RRMS compared to the control group were 76.73 ± 8.50 versus 105.58 ± 8.71 (P < 0.01), and patients with PMS compared to the control group were 72.56 ± 6.44 versus 105.58 ± 8.71 (P < 0.01). In patients with RRMS, the factors affecting the emergence of cognitive dysfunction included disability, fatigue, depression, and duration of illness, whereas in patients with PMS, just the disability variable was related to the presence or absence of cognitive dysfunction. Conclusions Our findings showed that disability, fatigue, depression, and duration of illness were factors associated with cognitive dysfunction in patients with RRMS. Proper identification of these factors can be helpful in the screening of cognitive dysfunction in this population.