Objectives To revise Korean Medication Algorithm Project for Depressive Disorder 2017 (KMAPDD 2017) guidelines by revising antidepressant choices based on their safety, adverse effects, comorbid physical illnesses, and the clinical definition of treatment-resistant depression (TRD). Methods A 33-item questionnaire comprised of six parts was developed. A 65-expert consensus (65/97, 67.0%) was obtained on pharmacological treatment strategies regarding antidepressant choice with respect to safety, adverse effects, and comorbid physical illnesses. Multiple response sets were subjected to statistical analysis. Results The results obtained showed that first-line pharmacotherapeutic strategies based on various clinical considerations were as follows: mirtazapine (for patients with increased suicidality, Gastrointestinal discomfort, and insomnia), bupropion (for patients with orthostatic hypotension, history of a safety accident, serotonin syndrome, sedation, sexual dysfunction, and weight gain), and escitalopram (for patients with anticholinergic side effects). For patients exhibiting comorbid conditions, duloxetine was the first line pharmacotherapeutic strategy for chronic pain, escitalopram was the first-line pharmacotherapeutic strategy for diabetes, hypertension, liver disease, Parkinson’s disease, renal disease, epilepsy, and thyroid disease, and sertraline was a first-line pharmacotherapeutic strategy for arrhythmia and cardiovascular disease. Conclusion Pharmacological treatment strategy of KMAP-DD 2021 is similar to that of KMAPDD 2017. Additional study is required to determine antidepressant choices for TRD and cancer patients with depression.