OBJECTIVE: To investigate the clinical value of immunoglobulin quantification, serum protein electrophoresis (SPE), and immunofixation electrophoresis (IFE) in the diagnosis of multiple myeloma (MM). METHODS: The clinical data of 75 patients suspected of MM in our hospital from January 2020 to May 2022 were retrospectively analyzed, all of whom received immunoglobulin quantification, IFE, and SPE. Based on the results of the patients' final bone marrow smears, MM‐positive patients were set as the MM group (30 patients), and MM‐negative patients were set as the control group (45 patients). The immunoglobulin levels and the results of IFE and SPE in the two groups were compared to analyze the efficacy of different diagnostic methods for MM. RESULTS: The differences in complement C3 and C4 between the two groups were not statistically significant, and the immunoglobulins in the MM group were lower than those in the control group (P < 0.05). The abnormal rates of IFE and SPE bands in the MM group were higher than those in the control group (P < 0.05). The compliance rate, sensitivity, specificity, positive predictive value, and negative predictive value of immunoglobulin quantification + IFE + SPE for MM diagnosis were higher than those of immunoglobulin quantification and immunoglobulin quantification + SPE (P < 0.05). Receiver operating characteristic (ROC) curve showed that the area under the curve (AUC) of immunoglobulin quantification + IFE + SPE for MM diagnosis was 0.923 (95% CI:0.885 to 0.930), the AUC of immunoglobulin quantification + SPE was 0.747 (95% CI:0.877 to 0.929), and the AUC of immunoglobulin quantification was 0.547 (95% CI:0.850 to 0.935). CONCLUSION: The clinical value of immunoglobulin quantification, IFE, and SPE in MM diagnosis is high. Immunoglobulin quantification and SPE can provide initial screening of MM, while the combination of IFE examination can improve the diagnostic accuracy of MM.