BACKGROUND: Although uncommon, osteolytic lesions with fluid-fluid levels may be caused by several different clinical entities and pose a true diagnostic challenge. OBJECTIVES: To systematically review case reports and case series of patients with multiple osteolytic lesions with fluid-fluid levels. DATA SOURCES: Medline, Web of Science, SciELO and OpenGrey. STUDY ELIGIBILITY CRITERIA: All published case reports and case series of patients with multiple osteolytic lesions with fluid-fluid levels. PARTICIPANTS: Patients with multiple osteolytic lesions with fluid-fluid levels. ANALYTICAL APPROACH: Descriptive analysis. RESULTS: After deduplication, a total of 363 references were found. From those, 8 studies were included, yielding 8 patients: 75% (6 patients) were female and the mean age was 50 years (range: 8 months – 76 years). Bone metastasis (62,5%, 6 patients) and brown tumours (25%, 2 patients) were the most frequent diagnoses. Other diagnoses were Langerhans cell histiocytosis (12,5%, 1 patient). LIMITATIONS: Lack of access to text of 2 published articles. CONCLUSIONS: This systematic review demonstrates that fluid-fluid level osteolytic lesions are more frequently found in female adults with malign conditions, commonly worthy of further treatment. Nevertheless, benign causes are also possible and, due to therapeutic and prognostic implications, should be pursued during the diagnostic investigation. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO register: CRD42015016535.