We described two cases of treatment-experienced HIV-infected patients who presented with cytomegalovirus uveitis and Cryptococcus neoformans adenitis as a manifestation of immune reconstitution inflammatory syndrome (IRIS) during salvage treatment. Little is known about IRIS in highly experienced patients, and this report suggests that IRIS should be considered in this setting if there is a favorable response to salvage therapy.We described two cases of treatment-experienced HIV-infected patients who presented with cytomegalovirus uveitis and Cryptococcus neoformans adenitis as a manifestation of immune reconstitution inflammatory syndrome (IRIS) during salvage treatment. Little is known about IRIS in highly experienced patients, and this report suggests that IRIS should be considered in this setting if there is a favorable response to salvage therapy.