To better understand the relationship between immunologic responses, immune reconstitution, and the occurrence of OIs, observational data need to be collected (1) in patients who present with an OI before initiation of potent antiretroviral therapy, (2) in patients with a history of such OIs who have had secondary prophylaxis or maintenance therapy withdrawn and do not develop OI recurrence after potent antiretroviral therapy, and (3) in controls who were exposed to the pathogen of interest but never were at risk for disease because their immunity was not severely compromised. Immunologic comparisons may identify correlates of protection for a group of patients who do not develop an OI after potent antiretroviral therapy-induced immune reconstitution. Conversely, a subpopulation of patients may be identified that lacks critical host factors of protection and is more likely to develop an OI after immune reconstitution, and therefore would benefit from continued prophylaxis, regardless of CD4 cell count.