Background: The incidence of cryptococcal meningitis among immunocompetent patients increases, especially in China and imaging plays an important role. The current study was to find the correlation between magnetic resonance imaging (MRI) manifestation and clinical severity in nonhuman immunodeficiency virus patients with cryptococcal infection of central nervous system (CNS). Methods: A total of 65 patients with CNS cryptococcal infection from August 2014 to October 2016 were retrospectively included in this study. All the patients had MRI data and clinical data. The patients were divided into two groups according to whether the patients were confirmed with identifiable underlying disease. Comparison and correlation of MRI and clinical data in both groups were investigated using independent sample t?test, Chi-square test, Mann-Whitney test and Spearman rank correlation analysis. Results: In all 65 patients, 41 cases (41/65, 63.1%;Group 1) had normal immunity and 24 cases (24/65, 36.9%;Group 2) had at least one identifiable underlying disease. Fever, higher percentage of neutrophil (NEUT) in white blood cell (WBC), and increased cell number of cerebral spinal fluid (CSF) were much common in patients with underlying disease (Group 1 vs. Group 2: Fever: 21/41 vs. 21/24, χ2 = 8.715, P = 0.003;NEUT in WBC: 73.15% vs. 79.60%, Z = ?2.370, P = 0.018;cell number of CSF: 19 vs. 200, Z = ?4.298, P < 0.001;respectively). Compared to the patients with normal immunity, the lesions are more common in the basal ganglia among patients with identifiable underlying disease (Group 1 vs. Group 2: 20/41 vs. 20/24, χ2 = 7.636, P = 0.006). The number of the involved brain areas in patients with identifiable underlying disease were well correlated with the number of cells and pressure of CSF (r = ?0.472, P = 0.031;r = 0.779, P = 0.039;respectively). Conclusions: With the increased number of the involved brain areas in patients with identifiable underlying disease, the body has lower immunity against the organism which might result in higher intracranial pressure and more severe clinical status.