Functioning can be defined as the ability to perform daily activities, and to maintain interpersonal relationships and work capacity/productivity. Major Depressive Disorder (MDD) is associated with substantial impairment in functioning. The study examined associations between various measures of functioning (patient assessment) and MDD symptoms (clinician assessment). A major challenge was to ensure MDD patient compliance with regular self-assessments and retention in a long-term study. OBJECTIVES: The purpose of the Direct to Patient Contact (DPC) approach was to maximize patient compliance to Patient Reported Outcomes (PRO) data collection and retention in a study conducted in real life settings over a two-year follow-up period. METHODS: This was an international, multicentric, observational, prospective longitudinal cohort study involving 1,500 MDD patients followed-up for two years in five European countries. Patients were recruited by General Practitioners or psychiatrists and data collected using a hybrid method: clinical data by physicians and PRO data self-assessment by patients. DPC actions included PRO questionnaire shipments to patients at five time points, followed by phone reminder contacts for non-returned questionnaires. RESULTS:  1,450 patients were included in the study, 97.8% of whom agreed to be contacted directly by DPC staff. Overall, 71.7% of patients were reached by phone and 75.6% of PRO questionnaires were returned; the questionnaire completion rate reached 95.3%. 79.6% of patients remained until study end, 0.1% died, 3.5% voluntarily withdrew from the study and 16.7% were withdrawn for other reasons. There were no patients lost to follow up. CONCLUSIONS: This study demonstrates that the use of DPC in a MDD population, likely to be study non-compliant/unresponsive, produced excellent long-term response rates. It minimized voluntary patient drop-outs and lost to follow up rates, and ensured an enhanced data collection of self-assessed PROs, thus improved reliability of study outcomes.