Aim: Affective disorders such as depression and anxiety are one of the most prevalent symptoms observed in patients following coronavirus disease 2019 (COVID-19). The aim of the TELESPHOR study was to evaluate the antidepressant effectiveness and tolerability of agomelatine therapy in daily clinical practice in patients with major depressive episodes (MDE) post-COVID-19. Methods: This multicenter, observational study enrolled outpatients aged 18-65 years who experienced an MDE (17 item Hamilton Rating Scale for Depression [HAMD-17] total score of 8-24) within 3 months of laboratory confirmed SARS-CoV-2 infection and who had initiated treatment with agomelatine. Study visits occurred at weeks 2, 4 and 8. The primary outcome was the antidepressant effectiveness of agomelatine assessed by change in HAMD-17 total score at week 8. Secondary outcomes included changes in HAMD-17 item 10 (anxiety psychic) and item 11 (anxiety somatic), the proportion of responders (≥50% decrease in baseline HAMD-17) and remitters (HAMD-17 score ≤7 at week 8), and impact on quality of life (QoL) (Short Form Survey [SF-36] questionnaire). Tolerability was assessed at each study visit. Results: The full analysis set comprised 103 patients of whom 73 (70.9%) were women. Median age was 45 years, and in the past 3 months 81 (78.6%) had experienced mild and 22 (21.4%) moderate COVID-19. The mean time from onset of infection to study inclusion was 2.1±0.7 months. At study entry, 55 (53.4%) had mild and 48 (46.6%) had moderate MDE. Agomelatine was associated with a significant improvement in depression severity with decreases in mean total HAMD-17 score compared with baseline of 2.6±3.3, 6.7±5.3, and 10.9±4.9 at weeks 2, 4, and 8, respectively (P<0.0001 for all). Significant reductions in anxiety psychic and anxiety somatic were also observed. Mental and physical components of SF-36 were significantly improved compared with baseline (P<0.0001). The proportion of responders was 81.4% and the proportion of remitters was 71.6%. Agomelatine was well tolerated over the 8-week follow-up. Conclusion: Treatment with agomelatine was associated with rapid and significant antidepressive and anxiolytic effectiveness, improved QoL, and good tolerability in the treatment of patients with an MDE after COVID-19.