Rationale: Intracranial infections are associated with high morbidity and mortality in immunocompromised patients, due to delayed diagnosis and treatment. Establishing a rapid, accurate diagnosis and a precise therapeutic regimen is crucial for management of the patients. Our report described a rare intracranial infection of patient with nephrotic syndrome. Patient concerns: A 66-year-old woman with a history of nephrotic syndrome presented symptoms in central nervous system for 1 month, followed by headache and fever over several days. Diagnosis: Neurological examination, brain imaging, and cerebrospinal fluid (CSF) tests exhibited resemblance to intracranial infection. Subsequently, CSF cultures confirmed the presence of Cryptococcus. Fortunately, next-generation sequencing revealed the concomitant infection with Nocardia farcinica in addition to Cryptococcus neoformans. Interventions: The treatment with intravenous fluconazole combined with amphotericin could not immediately ameliorate her symptoms. The patient's condition improved significantly with minimal deficits after timely administration of antibiotics against N farcinica. Outcomes: One month later, cranial MRI indicated that basal ganglia lesions ameliorated. The patient has recovered well. Lessons subsections: To our best knowledge, this is the first case report of intracranial infection caused by both N farcinica and C neoformans in a patient with nephrotic syndrome. Remarkably, extensive application of next-generation sequencing can facilitate investigation on the potential role of various pathogenic organisms in infectious diseases.