Introduction: Penicilliosis is an one of opportunistic infection with high mortality if left untreated, caused by infection of Penicillium marneffei. Penicilliosis in AIDS patients was first reported by Piehl in 1988, described as having symptoms of persistent fever, anorexia, and papular rash on the skin. Culture of blood, bone marrow, sputum and skin specimens all showed P. marneffei. Factors affecting penicilliosis infection in HIV patients are environmental predictors and levels of Cluster Differentiation (CD4). Therefore we were interested in examining the relationship between CD4 levels, which reflecting the immune state of an individual, with the incidence of penicilliosis in HIV patients. Method: This study was an observational analytic study with a cross sectional design to determine the relationship between CD4 levels and the incidence of penicilliosis in HIV patients. The population in this study were HIV patients in Haji Adam Malik Medan Hospital admitted since 2014 to 2018 aged ≥ 18 years. All patients had the CD4+ level tested, as well as the biopsy of skin lesion for P. marneffei. Result: Of 2859 research subjects, it was found that patients with positive touch biopsy who had CD4 levels <100 cells / µL is 32 patients which is 2.5% of all patients with CD levels <100 cells / µL. There were no patients with positive biopsy results who had CD4 cells ≥100 cells / µL (0.0%). Conclusion: There was a statistically significant correlation between CD4 levels and the incidence of penicilliosis (p = 0.001).