Objective To compare the clinical features of patients with early-onset and late-onset treatment-resistant depression. Methods Three hundred and seventy adult patients with treatment-resistant depression were divided into the early-onset group (n=193) and late-onset group (n=177) by the median method. The clinical features of two groups were compared and analyzed. Results Compared to the late-onset group, the proportions of male, introverts, and patients who completed nine-year voluntary education of early-onset group were higher (P<0.001) and the current episodes were longer, i.e. (17.32±25.94) months and (12.47±18.42) months, respectively (P=0.015). Compared to the early-onset group, the proportion of married patients, Hamilton depressive scale-17 items (HAMD-17) scores of depression level, and factor sleep disorder scores of late-onset group were all significantly increased (P<0.001), and the proportion of physical comorbidities was much higher (P=0.008). Conclusion The clinical features of patients with early-onset and late-onset treatment-resistant depression are different. The differences may be relevant to the potential pathophysiological mechanisms.