BACKGROUND: Major Depression (MD) is often a chronic condition requiring a long-term pharmacologic treatment. Despite the efficacy of antidepressants, the medication adherence in those affected is usually very poor. In this scenario, further research concerning drivers of suboptimal adherence is needed. We aimed to explore medication adherence in patients with a MD episode, and to identify sociodemographic, clinical (psychiatric antecedents, comorbidities, medication, pain, and medication side effects), and psychosocial factors (negative life events, childhood trauma, and attitudes to medication) related to adherence status. METHOD: The Medication Adherence Rating Scale (MARS) was completed by 370 patients at hospital admission. Participants were divided into groups of optimal and suboptimal adherence based on the medication adherence behavior score (MARS's factor 1), and were compared with respect to the study variables. RESULTS: Twenty-nine percent of participants (n = 107) were found to be optimally adherents to their medication (score = 4/4). Compared to optimally adherents, suboptimally adherents (71%) presented a significantly higher depression severity, more psychiatric hospitalizations, suicidal ideation, physical pain, negative medication side effects, and antecedents of emotional maltreatment. Suboptimally adherents also had less favorable attitudes toward medication and were less in a relationship than optimally adherents. Multivariate analyses showed that depression severity, suicidal ideation, and physical pain increase the probability of belonging to the suboptimal adherent group. CONCLUSION: These results suggest a vicious circle in which more vulnerable patients are less adherent to medication, which could worsen the clinical picture maintaining, in turn, low adherence. More efforts are needed to develop interventions aiming to improve medication adherence in MD patients.