Measures have been taken to reduce the mortality rate of Human Immunodeficiency Virus-infected clients. The use of isoniazid preventive therapy was one of those measures. Irrespective of using isoniazid preventive therapy mortality rate increased. The aim of this article is to analyse the causes and the factors that led to mortality among Human Immunodeficiency Virus-infected people who received isoniazid preventive therapy. A retrospective quantitative, explorative, descriptive isoniazid preventive therapy design was used. The records of 80 deceased patients who received isoniazid preventive therapy were reviewed through the use of a checklist. Of the records (N = 80), 75% were for female. The most highly indicated causes of death were gastroenteritis (18.75%), cryptococcal meningitis (17.5%) and pneumonia (16.25%). The causes of death of the patients who died before completing the six months of isoniazid preventive therapy; (28.75%) were gastroenteritis (21.7%), symptoms and signs of bacterial pneumonia (17.4%), cryptococcal meningitis (13%), pulmonary tuberculosis (13%), septicaemia (13%), and murder (13%). A breakdown in isoniazid preventive therapy, cotrimoxazole prophylaxis therapy and antiretroviral therapy interventions and the lack of holistic care for people living with Human Immunodeficiency Virus led to opportunistic infections leading to mortality among patients receiving isoniazid preventive therapy. A reorganisation of services of care for Human Immunodeficiency Virus-infected persons, such as provision of cotrimazole prophylaxis therapy and isoniazid preventive therapy to ensure a holistic approach to care, is recommended.