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Purpose: To determine the effects of combined use of cognitive behavioral therapy (CBT) and paroxetine hydrochloride tablets in patients with post-stroke depression (PSD), and its effect on scores on Hamilton Rating Scale for Depression (HAMD) and Stroke Specific Quality of Life Scale (SS-QOL). Methods: Clinical data for 96 patients with PSD who were treated in Dongying Traditional Chinese Hospital, Dongying City, China from June 2018 to June 2019 were retrospectively analyzed. Patients who met the inclusion criteria were divided into treatment group (TG, n = 48) and reference group (RG, n = 48) based on odd and even hospitalization numbers. Both groups received conventional treatment, but RG patients were in addition given clopidogrel, while TG received CBT in combination with paroxetine hydrochloride tablets. Clinical indices were evaluated in both groups before and after treatment. Moreover, therapeutic effects in the two different treatment methods on PSD, as well as on Hamilton Rating Scale for Depression (HAMD) and Stroke Specific Quality of Life Scale (SS-QOL) scores were analyzed. Results: After treatment, TG had lower HAMD score (p < 0.001), lower scores on modified Rankin scale, and few incidences of adverse reactions at 3, 7, 15 and 30 days of treatment (p < 0.05), but higher total clinical effectiveness and mean SS-QOL score (p < 0.05), when compared with RG. Conclusion: Combined use of CBT and oral paroxetine hydrochloride tablets may be a promising strategy for treating depression and enhancing the quality of life of PSD patients, as it greatly improves neurological deficit and prognosis. However, further clinical trials should be carried out prior to introducing it in clinical practice. [ABSTRACT FROM AUTHOR]