Introduction: With universal access to first line antiretroviral therapy need for second and third line regimen are increasing. Non-adherence, drug resistance and independent factors like age at start of therapy, low education level and HIV RNA viral load contribute to the second line anti-retroviral therapy failure wherein third line drugs are needed to be started as salvage therapy. Protease inhibitors used in second line therapy can fail due to primary mutation which can be detected with the help of drug resistance testing. Case Report: 45 years old HIV infected soldier developed first line anti-retroviral therapy failure five years after the start of drugs due to common mutations to non-nucleoside and nucleoside reverse transcriptase inhibitor like K103N, M184V, M41L, D67N, V75M. Thereafter two years of start of second line anti- retroviral therapy consisting of boosted protease inhibitor (lopinavir/ ritonavir) he developed immunological and virologic failure with drug resistance testing showing primary mutation to protease inhibitor (lopinavir/ ritonavir) as L24I, L33F, V82S and M46I. Third line anti- retroviral therapy was started consisting of boosted darunavir, raltegravir with tenofovir and lamivudine as nucleoside reverse transcriptase inhibitor backbone. Three months post therapy his HIV RNA viral load have decreased from 4,81,879 copies/mL to 9,563 copies/mL. Conclusion: Emergence of protease inhibitor resistance during second line anti-retroviral therapy need to be monitored with the help of clinical and virologic monitoring and third line drugs should be used as salvage therapy if adequate viral suppression has not been achieved.