Major depressive disorder (MDD) is a common recurrent mental disorder and one of the leading causes of disability in the world. The recurrence of MDD is associated with increased psychological and social burden, limitations for the patient, family, and society; therefore, action to reduce and prevent the recurrence of this disorder or hospital readmissions for depression among the patients is essential. The data of this retrospective cohort study were extracted from records of 1005 patients with MDD hospitalized in Farshchian hospital in Hamadan city, Iran (2011-2018). The hospital readmissions rate due to depression episodes was modeled using generalized Poisson regression (GPR). Demographic and clinical characteristics of the patients were considered as explanatory variables. SAS v9.4 was used (P < 0.05). A majority of the patients were male (66.37%). The mean (standard deviation) of age at onset of MDD and the average number of hospital readmissions were 32.39 (13.03) years and 0.53 (1.84), respectively (most patients (74.3%) did not experience hospital readmissions). According to the results of the GPR, the lower age at the onset of the disease (IRR = 1.02;P = 0.008), illiteracy (IRR = 2.06;P = 0.003), living in urban areas (IRR = 1.56;P = 0.015), history of psychiatric illnesses in the family (IRR = 1.75;P = 0.004), history of emotional problems (IRR = 1.42;P = 0.028) and having medical disorders (IRR = 1.44;P = 0.035) were positively associated with the number of hospitalizations. According to our findings, urbanization, early onset of the disease, illiteracy, family history of mental illness, emotional problems, and medical disorders are among major risk factors associated with an increased number of hospital readmissions of MDD.