This study aimed to assess the prevalence of and factors associated with tobacco use among patients living with HIV/HCV co-infection. Patient reported outcomes (PROs) were analyzed of patients living with HIV/HCV co-infection (n = 313) who presented for clinical evaluation and treatment of HCV between 2013 and 2017 at a university-affiliated HIV/HCV Co-infection Clinic. The prevalence of tobacco use in patients living with HIV/HCV co-infection was 48%. Compared to non-smokers, a higher proportion of tobacco smokers had substance use disorders and concurrent alcohol and substance use. In the multivariate analysis, concurrent alcohol and substance use was positively associated with tobacco use. The findings suggest clinical interventions are urgently needed to reduce tobacco use among patients living with HIV/HCV co-infection—a doubly-vulnerable immunocompromised population. Otherwise, failed efforts to dedicate resources and targeted behavioral interventions for this respective population will inhibit survival—especially considering the recent and evolving COVID-19 pandemic.