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Nascent studies showed that patients with chronic medical illnesses such as diabetes mellitus (DM) and HIV/AIDS are highly vulnerable to face both treatment burden and regimen fatigue. However, an attempt made so far in this sphere in sub-Saharan African health care context is dearth. Thus, this study aimed to determine the level of treatment burden and regimen fatigue of diabetic and HIV patients attending adult diabetic and ART clinics of TASH and explore patients' and health care workers' propositions to reduce treatment burden and regimen fatigue. An explanatory sequential mixed methods study was conducted at the adult HIV and DM clinics of TASH, Addis Ababa, Ethiopia from February 01-March 30, 2022. Simple random and purposive sampling techniques were employed to select participants for quantitative and qualitative studies, respectively. Descriptive analysis was done to summarize the quantitative data. Logistic and linear regression analyses were performed to identify predictors of treatment burden and regimen fatigue, respectively. P value < 0.05 was considered statistically significant. Qualitative data was analyzed by using a thematic analysis. A total of 300 patients (200 diabetes and 100 HIV) were included in the quantitative study. For the qualitative study, 14 patients and 10 health care workers (six nurses and four medical doctors) were included. Participants' mean global Treatment Burden Questionnaire (TBQ) and Treatment Regimen Fatigue Scale (TRFS) score were 28.86 ± 22.13 and - 42.82 ± 17.45, respectively. Roughly, 12% of patients experienced a high treatment burden. The presence of two or more comorbidities (adjusted odds ratio [AOR] = 7.95, 95% confidence interval [CI] 1.59-39.08), daily ingestion of more than five types of prescribed medications (AOR = 6.81, 95%CI 1.59-29.14), and good knowledge about DM and/or HIV (AOR = 0.33, 95%CI 0.12-0.92) were predictors of treatment burden. Poor availability of medications (β = 0.951, p < 0.001) was the only predictor of regimen fatigue. Patients and health care workers primarily proposed to foster self-care efficacy, advance administrative services of the clinic and hospital, and improve healthcare system provision. The findings of this study unveiled that a considerable proportion of patients experienced low levels of treatment burden and regimen fatigue. This study showed that boosting the patients' self-care efficacy, upgrading administrative services of the clinic and hospital, and promoting the healthcare system provision had enormous significance in reducing treatment burden and regimen fatigue. Therefore, when designing patient-specific healthcare interventions for both HIV and diabetic patients' various factors affecting both treatment burden and regimen fatigue should be considered to achieve the desired goals of therapy., (© 2024. The Author(s).)