Objective To assess the clinical benefit and compare the cost-effectiveness of total knee arthroplasty (TKA) in patients with different personality traits. Methods The present study was retrospectively conducted from January 2017 to May 2018. A total of 232 patients between 46 and 71 years old who underwent unilateral, primary TKA with the diagnosis of knee osteoarthritis were interviewed. Three types of data were required to compare the cost-effectiveness differences among groups: personality traits, postoperative clinical outcomes about health-related quality of life, and costs associated with TKA. Personality was assessed using the Eysenck Personality Questionnaire, functional outcome was assessed through the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire, and costs were evaluated. Besides, the marginal cost-effectiveness ratio (MCER) as the primary outcome, which relates the direct costs to the associated patient benefit as assessed by the clinical endpoint ($/quality-adjusted life years [QALY]), was compared among different personality traits. All information for this study was acquired by directly interviewing the patients and reviewing the medical computer records at our hospital. Results Two hundred and eleven patients completed the final analysis with an average of 24.6 months follow-up postoperatively. The choleric group, sanguine group, melancholic group, and phlegmatic group has 41, 70, 46, and 54 patients, respectively. A statistically significant difference in MECR, QALYs, and postoperative WOMAC existed among different personality traits (all P < 0.05). There was no significant difference in mean age (P = 0.588), body mass index (BMI) (P = 0.790), smoking (P = 0.934), heavy drinking (P = 0.994), chronic comorbidities (all P > 0.05), preoperative albumin <3.5 g/dL (P = 0.991), and American Society of Anaesthesiologists (ASA) score (P = 0.687) among personality traits. More women tend to be melancholic in comparison to other personality traits (P = 0.016). Melancholic patients attested inferiority of TKA compared with other personality traits, who would pay for the same QALYs at the highest costs (P < 0.05). By contrast, sanguine patients have a more cost-effective TKA than other personality traits, as they pay the least money for the same QALYs (P < 0.05). Although phlegmatic and choleric patients seemingly have moderate gains from TKA, in general, the extroversion (measured by the extroversion subscale) and stability (measured by the neuroticism subscale) displayed more pleasurable QALYs in comparison with introversion and instability (P < 0.05). Sensitivity analysis showed that the results mentioned above appeared not to be sensitive when varying key parameters (prosthesis survival and life expectancy) in a one-way sensitivity analysis. Sanguine and melancholic patients still have the lowest and highest MCER in comparison with choleric and phlegmatic traits (P < 0.05). The multivariate logistic regression showed that RA (adjusted OR = 1.3, 95% CI = 1.2-1.4, P < 0.01), ASA Class I-II (adjusted OR = 0.9, 95% CI = 0.8-1.0, P < 0.001), sanguine (adjusted OR = 0.8, 95% CI = 0.7-0.9, P < 0.001) and melancholic (adjusted OR = 1.2, 95% CI = 1.1-1.3, P < 0.001) were significantly associated with MCER. Conclusions Before surgery, screening the melancholic patients would significantly reduce the economic burden, avoid unnecessary suffering, and shorten the recovery period.