Patients with HIV and opportunistic infections (OIs), such as tuberculosis and cryptococcosis, have been recognised to have immune reconstitution inflammatory syndrome (IRIS) following initiation of highly active antiretroviral therapy (HAART). The initiation of HAART boosts CD4 T cells, which result in exacerbations of OIs. We have identified deterioration of neural lesion in imaging after the initiation of HAART in a patient with HIV/cryptococcal infection, although patient's clinical conditions have not deteriorated. It is evident that IRIS is in subtlety. This has been possible because of prompt treatment with antifungal drugs for the cryptococcal infection, followed by early initiation of HAART.