Objective: To analyze the rationality of antimicrobial (AM) and respiratory (RP) fixed dose combinations (FDCs) available in Indian market. Materials and Methods: Antimicrobial and RP FDCs enlisted in Indian Drug Review 2010 and 2013 respectively were analyzed by a pretested validated 8 point criteria tool. Each FDC was assessed for number of active pharmacological ingredients, approval by regulatory authority, listing in World Health Organization (WHO) essential medicine list (EML) or National List of Essential Medicine. While efficacy, safety, pharmacokinetic and pharmacodynamic interactions and advantages of each FDC were analyzed by evidence based literature search. Each criterion was scored one for positive and minus one for negative or unfavorable observation. The total score for the tool was 12 and score ≥7 was considered rational. Results: Of 209 FDCs, 108 were AMs and 101 were RPs. The mean rationality score was 5.41 ± 1.63 (95% CI, 2.15-8.67). Majority of FDCs were irrational (174) while 35 were rational, and only 12 of these were listed in WHO EML 2013. Out of 108 AM FDCs, 21 (19%) were rational while 87 (81%) were irrational. Out of 101 RP FDCs, 14 (14%) were rational while 87 (86%) were irrational and 24 (24%) with unfavorable pharmacodynamic interactions. Majority of the rational AM FDCs were antiretroviral (6) agents while RP FDCs were indicated for chronic obstructive pulmonary diseases. While majority of irrational FDCs were AM plus steroids, β2 agonists plus antihistaminics/expectorants/anticholinergics/mast cell stabilizers/leukotriene receptor antagonists. Conclusion: Rationality assessment of AM and RP FDCs reveals that a substantial number of these FDCs in Indian market are irrational. This calls for a close scrutiny of marketed FDCs and educating prescribers to use them with great care and caution. This also indicates a serious review of the regulatory framework for drug manufacturing and marketing.