Fatigue during pregnancy is most common during the first trimester. It tends to go away during the second trimester, but will usually return in the third trimester. During early pregnancy, hormonal changes are likely the cause of fatigue. This study aimed to assess fatigue in pregnancy and its main determinants in women who attended in health centers of Hamadan city, Iran, 2015. This case–control study was conducted on 126 pregnant women (case: with fatigue, n = 40; control: without fatigue, n = 86) who attended prenatal care clinic for routine follow-up in health centers. The cluster sampling was used. Information was collected by interviewing and using a standardized validated questionnaire. Severity of fatigue was assessed through using questionnaire. Data processing and statistical analysis were performed by using SPSS/ 20.0. The results revealed that majority of women experienced fatigue during pregnancy. In a multivariable logistic regression model, age, education, husband s education, parity, Income, pre pregnancy weight, height, body mass index (BMI), and smoking were main determinants of fatigue during pregnancy. Most of pregnant women suffered fatigue during pregnancy which severity can be determined by advanced age, parity, pre pregnancy weight, BMI, and decreased income.