The main objective of the present study was to perform and improve the rationality by looking for potential Drug-Drug Interactions and Adverse Drug Reactions associated with Anti-Retroviral Therapy and increase the adherence among Human Immunodeficiency Virus (HIV) patients attending to the Anti-Retroviral Therapy (ART) centre in south India. A prospective observational study was conducted in the city of Vijayawada, South India to assess the Adverse Drug Reactions (ADR's) and Drug-Drug interactions (DDI's) among the patients receiving Highly Active Anti RetroviralAnti-Retroviral Therapy (HAART) using approved scales and databases. A total of 530 patients were screened in a span of 1 year, resulting in 394 ADR's and 385 DDI's among the various drugs being used.The most commonly used drug combination was Tenofivir + Lamivudine + Efavirenz (63.3%). In looking at the reported ADR's the majority of them were mild in terms of severity, preventability and causality and none of the DDI's were severe enough to bring a change in the therapy. Statistical analysis was performed using SPSS 16 version by using Chi-square test. The risk caused by the associated ADR's and DDI's are observed and proven to be not deleterious in most of the cases. If adequate knowledge, prompt treatment and in-depth analysis of the associated risk factors and personal history were considered the HAART would be definitely more successful.