Cryptococcus neoformans is the most incriminated fungal pathogen causing meningitis in acquired immune deficiency syndrome (AIDS) patients, and is known to constitute a major cause of deaths in AIDS patients. This study aimed to determine the sero-prevalence and effect of CD4 count on seropositivity for Cryptococcus neoformans antigen (crag) in antiretroviral- naïve (ART-naïve) AIDS patients. This study included 150 (61 males and 89 females) ART-naïve AIDS patients attending the Human Immunodeficiency Virus (HIV) clinic of the University of Benin teaching hospital, Benin City, Nigeria within the period February 2011- July 2011. 40 (18 males and 22 females) HIV positive outpatients with CD4 counts >200 cells/µl who are ART-naive were recruited and used as controls. The prevalence of crag in the patients and control group was determined using the cryptococcal antigen latex agglutination system (CALAS) (Meridian Bioscience, Europe) and CD4 counts were measured using flow cytometry (Partec flow cytometer, Germany). Of 150 ART-naïve AIDS patients with CD4 counts ≤ 200 cells/µL, 19 (12.7%) were positive for serum Cryptococcal antigen. ART-naïve AIDS patients with CD4 count ≤50 cells/µl had the highest prevalence of serum crag. Lower CD4 counts were significantly associated with positivity for serum crag (P