Cryptococcus neoformans (C. neoformans) is a causative agent for acute pulmonary infection, which can further develop to lethal meningoencephalitis if untreated. The meningoencephalitis infection can be prevented, if timely treatment on pulmonary cryptococcal infection can be implemented based on its early diagnosis and accurate assessment. In this study, blood serum surface-enhanced Raman spectroscopy (SERS) method was investigated on identification and assessment of pulmonary C. neoformans infection. The serum SERS measurements were collected from the mice infected with C. neoformans and the healthy mice, in which the infected mice were further divided into four subgroups according to the duration of infection. Based on those SRES measurements, biochemical differences were analyzed among those different groups to investigate the potential biomarkers for identifying and assessing the pulmonary C. neoformans infection. Furthermore, partial least square (PLS) analysis followed by linear discriminant analysis (LDA) model was employed to identify pulmonary cryptococcal infection and to assess the degrees of infection with the accuracies of 96.7% and 85.3%, respectively. Therefore, our study Cryptococcus neoformans (C. neoformans) is a causative agent for acute pulmonary infection, which can further develop to lethal meningoencephalitis if untreated. The meningoencephalitis infection can be prevented, if timely treatment on pulmonary cryptococcal infection can be implemented based on its early diagnosis and accurate assessment. In this study, blood serum surface-enhanced Raman spectroscopy (SERS) method was investigated on identification and assessment of pulmonary C. neoformans infection. The serum SERS measurements were collected from the mice infected with C. neoformans and the healthy mice, in which the infected mice were further divided into four subgroups according to the duration of infection. Based on those SRES measurements, biochemical differences were analyzed among those different groups to investigate the potential biomarkers for identifying and assessing the pulmonary C. neoformans infection. Furthermore, partial least square (PLS) analysis followed by linear discriminant analysis (LDA) model was employed to identify pulmonary cryptococcal infection and to assess the degrees of infection with the accuracies of 96.7% and 85.3%, respectively. Therefore, our study has demonstrated the great clinical potential of using serum SERS technique for an accurate identification and assessment of pulmonary cryptococcal infection. (c) 2021 Elsevier B.V. All rights reserved.