Abstract Background The Bacillus Calmette-Guerin (BCG) vaccine is routinely administered to newborn infants in South Africa. In 2000, a new vaccine, the Danish 1331 strain, was introduced into the Western Cape region. Red Cross Children's Hospital subsequently documented an increase in the number of complications arising from the new vaccine. Since 2004, HIV-positive infants have been treated with highly active antiretroviral therapy (HAART). Coinciding with the roll out of HAART there has been a significant and apparently paradoxical worsening of the complications of the BCG vaccine. Methods A retrospective analysis of all HIV-positive infants referred to the surgical department for management of BCG vaccine complications. Results Fifteen infants were included in this study; they were all HIV-positive. Fourteen infants received HAART. In 10 patients, the implementation of HAART predated the complications of the BCG vaccine by an average of 1.4 months. Conclusion We believe this to be the first description of BCG-associated immune reconstitution inflammatory syndrome. The implications for the operating surgeon are the unique management strategies that should be applied to this disease process and the ongoing research to determine which of these strategies is the most effective.