A 54-year-old man of Greek origin presented with bone pain, headache, and epistaxis. Laboratory evaluation showed anemia (5.4 g/dL), thrombocytopenia (30 × 10 9/L), neutropenia (1.18 × 10 9/L), and immunoglobulin G λ paraprotein (68 g/L). Blood smear examination (panels A-D; original magnification ×500; May-Grünwald-Giemsa stain) demonstrated 27% atypical plasma cells (panel A), leading to the diagnosis of primary plasma cell leukemia. Initial red blood cell transfusion increased the hemoglobin (Hb) level (7.9 g/dL). Three days later, the Hb level was 4.7 g/dL with reticulocytes of 35.7 × 10 9/L (2.3%). Blood smear examination revealed the appearance of red blood cell so-called “hemighosts” (panels B-D, arrows [B]). These atypical red blood cells in which the Hb is confined to 1 side of the erythrocyte highly suggested hemolytic anemia due to glucose-6-phosphate dehydrogenase (G6PD) deficiency. Hemolysis was confirmed by the decrease of haptoglobin (<0.10 g/L) and cotrimoxazole was identified to be the trigger of this hemolytic crisis. Due to concomitant red blood cell transfusion, G6PD activity was only slightly decreased (10.7 IU/g Hb; reference range, 11-17). After 4 cycles of bortezomib, doxorubicin, dexamethasone, and cyclophosphamide which led to very-good-partial response, a moderate G6PD deficiency was confirmed (5 IU/g Hb).This case highlights the contribution of routine blood smear examination in the context of anemia. Testing G6PD activity is useful to confirm G6PD deficiency but may be falsely negative during hemolytic crisis or in the case of concomitant red blood cell transfusions.