To evaluate the relationship between disease duration, disability, disease pattern, age and sex with fatigue in MS patients. One hundred and seventy-three clinically definite MS patients and 87 age-matched healthy controls enrolled in this cross sectional study. Demographic data (sex, age), duration of the disease and disease pattern extracted from patient's files and Kurtzke Expanded Disability Status Scale (EDSS) were recorded for each patient by an expert neurologist. Participants were asked to answer the validated and reliable Persian version of beck depression inventory (BDI) and FSS (fatigue severity score) questionnaires. Mean FSS and BDI scores were significantly different between patients and controls (p < 0.001). Patients with longer disease duration, higher EDSS and progressive type of disease had significantly higher FSS and BDI scores. Although men had higher EDSS, FSS and BDI scores were similar in both sex groups. FSS was significantly correlated with age, disease duration, BDI and EDSS. The analysis of covariance revealed that there is no difference in the covariance-adjusted means for fatigue among two disease groups (relapsing remitting and secondary progressive) except for EDSS. MS patients with longer disease duration, higher EDSS and progressive type of disease suffer from fatigue more than cases with lower EDSS, duration of disease and relapsing type of the disease.