Background: The role played by social determinants of health including social, economic, environmental and cultural factors in influencing health outcomes for many health conditions has been widely described. However, the potential impact of these factors on morbidity and mortality of infectious diseases particularly tuberculosis (Tb)/HIV co-infection mortality is scantly addressed. We assessed the role that social determinants play in Tb/HIV co-infection mortality in southwest Ethiopia. Methods: A retrospective cohort study collated Tb and HIV data from Jimma University Teaching Hospital, Southwest Ethiopia for the period of September 2010 and August 2012. Data analysis was conducted using STATA version 14 for mackintosh. Both descriptive and inferential statistics analyses were performed. Logistic regression was applied to identify factors associated with Tb/HIV co-infection mortality at P value of ≤0.05 in the final model. Results: Fifty-five (20.2 %) patients died during the study period. Compared to their counterparts, more Tb/HIV co-infection death was observed in young age groups between 25 and 34 years (47.3 %), females (58.2 %), daily labors (40 %) and Muslim followers (54.5 %). 43.6 and 41.8 % of study participants respectively had single and double bedrooms, and 25.5 and 23.6 % of deceased study participants did not have water and electricity in the household respectively. Logistic regression analyses demonstrated the following factors significantly associated with Tb/HIV co-infection mortality: Being a commercial sex worker (AOR, 5.6; 95 % CI, 1.2-25.8), being of bed ridden functional status (AOR, 3.9; 95 % CI, 1.5-10.3) and being a rural resident (AOR, 3.4; 95 % CI, 1.4-8.4). Conclusions: One-fifth of Tb/HIV co-infected patients died due to the co-infection. Social determinants including type of occupation, severity of disease and residing in rural areas seemed to have a significant association with the poor disease outcome. Findings of this study inform the role that social determinants play in influencing mortality due to Tb/HIV co-infection. Consistent with principles of primary health care as stated by Alma Ata declaration, and in order to achieve better disease outcomes, intervention frameworks that address Tb/HIV mortality should not only focus on the medical interventions of diseases, but should also integrate and improve social determinants of affected populations.