Background and Objectives: Prevalence of Tuberculosis (TB) is quite high in various regions of the world. Fixed-dose combination (FDC) is highly recommended in various cases like TB, diabetes mellitus, hypertension, etc. Various studies are conducted to assess safety and efficacy of FDC. Likewise, prime focus of present review is to evaluate the potential disadvantages of FDC and compare it with single formulation (SF). Methods: We used a number of electronic databases to identify the relevant published studies which demonstrated the disadvantages regarding fixed dose combination for tuberculosis. Of 204 articles found initially, 143 were selected for additional review. Subsequently, 72 articles were finally selected. Results and Conclusions: Being a disease of poor, several advantages like cost-effectiveness, reduction in pill burden and logistical advantages, etc. can be achieved with FDC. Besides these advantages, there are several disadvantages like poor bioavailability, enzyme level elevation, adverse drug reactions, questionable effectiveness in the absence of Direct Observed Therapy Short course (DOTS) and therapeutic drug monitoring, difficulty in dose adjustment, etc. are associated with FDC. In such consequences there may be the need to reconsider the treatment regimen, otherwise conversion of TB into multi-drug resistant TB (MDR-TB) or extended drug resistant TB (XDR TB) occurs. Hence, it is concluded that FDC is neither superior nor inferior in terms of clinical outcomes and in certain situations the need of SF might not be replaced by FDC.