Objectives The aim of the review was to elucidate the adverse effects of chronic treatment with the main subclasses of highly active antiretroviral therapy (HAART). Methods A systematic review was carried out using the methods recommended in the Preferred Reporting Items for Systematic Review and Meta‐analysis Protocols (PRISMA‐P). Searches of articles in MEDLINE, SCIELO, Web of Science and LILACS were conducted from January to October 2018 based on the following descriptors and keywords: ‘HIV’ [AND]; ‘AIDS’ [OR]; ‘HAART’ [AND]; ‘Highly Active Antiretroviral Therapy’ [OR]; ‘Adverse Effects’ [AND]. All articles selected described the biochemical changes produced by, and the main adverse effects of, using one or more of the following HAART subclasses: nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs) and other new drugs. The selected articles included patients living with HIV (PLWH) initiating or continuing any type of HAART. The results are presented qualitatively and discussed. Results Twenty‐one articles found in the searches were selected for the review, and they included a total of 5626 participants. Seven of the studies investigated mainly NRTIs, three studies mainly NNRTIs, eight studies predominantly PIs, and three studies other antiretroviral drugs as the main treatment. The most common adverse effects on biochemical parameters were the emergence of anaemia for NRTIs as well as NNRTIs and PIs, and plasma lipid alterations caused by their prolonged use. In general, it was found that biological differences among individuals can cause differences in adverse effects, such as virological and treatment failure. Conclusions One or more occurrences of adverse effects of the chronic utilization of drugs were found for all subclasses of HAART, and certain combinations of drugs from different subclasses were also found to be associated with adverse events.