Cryptococcal meningitis (CM) is a common opportunistic infection in patients with acquired immune deficiency syndrome. Although there is a standardized treatment for CM, some patients still have CM-associated immune reconstitution inflammatory syndrome (IRIS) after anti-cryptococcal and antiretroviral therapy, which manifests as cognitive impairment. We report two cases of CM-associated IRIS in human immunodeficiency virus (HIV) patients that were treated with lenalidomide. The treatment yielded a rapid clinical remission and improved cognitive function in both patients; their Montreal Cognitive Assessment (MoCA) and International HIV Dementia Scale (IHDS) scores improved. Furthermore, we evaluated changes in 32 cytokines in the cerebrospinal fluid of two patients and found that both MoCA and IHDS were significantly negatively correlated with inflammation-related factors (growth-related oncogene, interleukin [IL]-10, IL-2, IL-8, macrophage inflammatory protein-1β, tumor necrosis factor [TNF]-α) and significantly positively correlated with dementia-related factors (αβ42 and total tau). Our study reveals the potential of lenalidomide in treating cognitive impairment caused by immune-mediated inflammation in patients with HIV-CM. Moreover, we speculate that lenalidomide improves cognitive function by regulating intracranial inflammation via multiple pathways, not only by TNF-α blocking.