HIV drug resistance is an emerging public health concern; appropriate ART combinations and safe drug switches are prerequisites for achieving virologic suppression. In the early 2000, in Sub-Saharan Africa, accent was mostly on prevention and the scale up of Antiretroviral therapy has just initiated. We report a 46-year-old female who was initiated on ART in 2005 in the private sector, had multiple regimens changes for unclear reasons. Over 7 years (2005-2012), she deteriorated and presented with an AIDS defining condition. A genotyping resistance test (GRT) revealed multiple HIV class resistance and was switched to a third-line ART and improved on treatment. This case report shows that the absence of formal ART guidelines in early 2000, long term exposure to ART and failure to timely switch led to treatment failure and development of multiclass drug resistance mutations identified by the HIV-1 GRT and guided the third-line ART regimen with a successful outcome.