TB/HIV co-infection is a very heavy burden, and controlling or even eliminating it is a challenge for African countries and their health services. The leading cause of mortality for those with TB/HIV co-infection is still resistance to anti-tuberculosis medications, and the factors leading to it are little known because they are less documented. The main aim of this research was to determine the drivers of multi-drug resistance to anti-tuberculosis drugs in TB/HIV co-infection in tuberculosis patients in a hospital in Kinshasa. A descriptive cross-sectional study analyzed 25 records of patients with TB/HIV co-infection undergoing antiretroviral and anti-tuberculosis treatment at the Saint-Pierre de Kabambarré Hospital in Kinshasa. The mentioned files were analyzed over a period running from October 2023 to January 2024. A descriptive analysis revealed that environmental variables, including alcohol intake, had contributed to 46.6% of patients' development of resistance to anti-tuberculosis medications, loss of sight due to relocation, compared with 40% as a result of economic factors, in particular poverty and geographical inaccessibility. Only 32% of resistance was linked to medical factors: stock-outs of anti-tuberculosis drugs, and 41% of respondents developed resistance as a result of biological factors. On the other hand, only 12% of patients developed resistant relapses due to socio-demographic factors, such as discrimination and the myth surrounding tuberculosis. Poverty combined with the global economic collapse, geographical inaccessibility, stock-outs of anti-tuberculosis drugs and antiretrovirals, increased viral load, discrimination and the myth surrounding tuberculosis are responsible for anti-tuberculosis drug resistance in patients with HIV/TB co-infection.