Early diagnosis and targeted preemptive antifungal treatment are crucial in reducing cryptococcal meningitis (CM)-related mortality in individuals living with human immunodeficiency virus (HIV). The present study was performed to determine cryptococcal antigenemia and outcomes among HIV-infected patients in Iran. This multicenter prospective study was conducted between October 2016 and December 2018. For the purpose of the study, blood samples were randomly collected from 177 profoundly immunosuppressed (CD4+ counts < 200 cells/mu L) HIV-positive individuals in six major cities of Iran. The patients were antiretroviral therapy-naive or had received inadequate medication. The stored sera were screened for cryptococcal antigen (CrAg), using point-of-care lateral flow assay (IMMY (R) diagnostics, Norman, OK, US). Overall, out of the 174 asymptomatic patients, 3 (1.72%) cases were CrAg-positive using the LFA in serum. Accordingly, the prevalence of cryptococcal antigenemia was 7.14%, 0%, and 1.2% in the patients with the CD4+ counts of < 50, 50-100, and 100-200 cells/mu L, respectively. The median age of the patients with antigenemia was 36 years (age range 8-55 years). The median CD4+ count of the cohort was 98 cells/mu L (range 14-200 cells/mu L). Routine screening of Iranian HIV-infected patients with CD4+ count of < 50 cells/mu L before initiating antiretroviral therapy is justified. It is suggested to conduct more inclusive research throughout the whole country on more patients to recommend screening cryptococcal antigen strongly.