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To describe MDD patients starting antidepressant (AD) treatment by pharmacological approach and identify factors associated with a longer sick leave (SL) duration. Retrospective study on IQVIA German Disease Analyser (specialists) and Spanish Longitudinal Patient Database (general practitioners and specialists). MDD patients initiating AD treatment between July 2016–June 2018 were grouped by therapeutic approach (AD monotherapy vs. combination/switch/add-on) and their characteristics were analysed descriptively. Multiple logistic regression models were run to evaluate factors affecting SL duration (i.e., >30 days). One thousand six hundred and eighty-five patients (monotherapy: 58%; combination/switch/add-on: 42%) met inclusion criteria for Germany, and 1817 for Spain (monotherapy: 83%; combination/switch/add-on: 17%). AD treatment influenced SL duration: combination/switch/add-on patients had a 2-fold and a 4-fold risk of having >30 days of SL than monotherapy patients, respectively in Germany and Spain. Patients with a gap of time between MDD diagnosis and AD treatment initiation had a higher likelihood of experiencing a longer SL both in Germany and Spain (38% higher likelihood and 6-fold risk of having >30 days of SL, respectively). A careful and timely selection of AD treatment approach at the time of MDD diagnosis may improve functional recovery and help to reduce SL, minimising the socio-economic burden of the disease. The major depressive disorder has a substantial impact on work absenteeism. The present study aimed to describe MDD patients starting antidepressant (AD) treatment depending on the pharmacological approach and to identify factors associated with longer sick leave (SL) duration. Patients receiving AD monotherapy had a lower likelihood of having more than 30 days of sick leave than those receiving AD combination/switch/add-on. Patients for whom a gap of time between MDD diagnosis and initiation of AD treatment was observed, showed a higher likelihood of having more than 30 days of sick leave. Because findings from this analysis relied on secondary data, the authors would like to claim the urgency of conducting prospective observational studies that further investigate the effect that different AD therapeutic approaches and timely initiation of treatment might exert on patients' recovery. [ABSTRACT FROM AUTHOR]