It is often difficult to distinguish infectious disease of the central nervous system from a wide variety of non-infectious diseases, as neurosurgeons have few opportunities to treat them. Differentiation of infectious diseases from neoplastic diseases is often challenging. Since it often takes time to eliminate infectious diseases, it is necessary to utilize all the obtained medical information to make a proper diagnosis to avoid missing the appropriate chance of surgical treatment. In this paper, we describe tips for and pitfalls of accurately distinguishing such diseases, including brain abscess versus glioblastoma, meningitis versus dural lesions, and infection versus lymphoproliferative disorders in immunocompromised patients. In these cases, it is difficult to make a decision based only on the examination and imaging findings on admission, and it is important to make a diagnosis based on medical history and patient background.