Rationale:Cold agglutinins are related with B cell lymphoproliferative disorder and lymphoma, and can agglutinate red blood cells (RBCs) at an optimum temperature of 3–4°C, which is the undergoing cause of RBCs cold agglutination. RBC cold agglutination may lead to an extreme abnormality of RBC parameters of complete blood count (CBC).Patient concerns:The present study reports a case of an old patient with severe infectious fever and anemia presenting extremely abnormal levels of RBC parameters in CBC and a sand-like appearance of blood on tube wall. The validating tests indicated the presence of the RBCs cold agglutination and the highly suspected B cell lymphoma.Diagnoses:The 37°C-incubation corrected the CBC results of the patient, and the microscopic observation and flow cytometry analysis of blood and marrow indicated many abnormal B lymphocytes. Subsequently, the patient was diagnosed with a highly suspected B-cell lymphoma.Interventions:The blood with a sand-like appearance was reanalyzed to validate the cold agglutination by 37°C-water incubation. The smears of peripheral blood and marrow were made for morphological observation by using optical microscopy. Moreover, the clusters of differentiation of the white blood cells were analyzed to confirm the type of abnormal white blood cells with a flow cytometer.Outcomes:The RBCs cold agglutination was validated, and the highly suspected B cell lymphoma was proved as the undergoing cause.Lessons:This case focuses on the discovery and solutions of RBCs cold agglutination, and emphasizes the importance of microscopic observation in the exploration of undergoing causes of cold agglutination.