In this study, the immunophenotype was retrospectively analyzed in 131 patients who received initial treatment for plasma cell myeloma (PCM) and the relationships of CD81 and CD117 with the clinicopathologic characteristics and prognosis were further evaluated. The Kaplan and Meier method and Cox regression survival analysis model were used to determine whether CD117 and CD81 were factors affecting the overall survival (OS) and progression‐free survival (PFS) of PCM patients. CD117 and CD81 positivity was demonstrated in 35.88% and 40.46% of the 131 patients, respectively. Kaplan‐Meier analysis showed that CD117 and CD81 were potential predictors of a patient's prognosis. Specifically, CD117(+) patients had longer PFS (P = 0.033) and OS (P = 0.002), while CD81(+) patients had shorter PFS (P = 0.001) and OS (P = 0.002). CD117(+) and CD81(−) patients had the longest PFS [P = 0.0183 compared to the CD117(−)CD81(−)/CD117(+)CD81(+) group; P = 0.0007 compared to the CD117(−)CD81(+) group] and the longest OS [P = 0.0331 compared to the CD117(−)CD81(−)/CD117(+)CD81(+) group; P = 0.0005 compared to the CD117(−)CD81(+) group]. Our results show that CD81 is an independent factor affecting the OS and PFS of PCM patients, and CD117 is an independent factor affecting the OS of PCM patients. CD117‐positive and CD81‐negative patients with PCM have a better prognosis.