Solitary plasmacytoma of bone (SPB) is a rare tumor that represents a minority of patients with plasma cell localized malignancy characterized by a single osteolytic bone lesion. The molecular mechanism underlying the genesis of SPB has remained enigmatic. Signal transducers and activators of transcription-3 (STAT3) is often activated in human cancers and is implicated in tumorigenesis. In the present work, the immunohistochemical expression of pSTAT3 (the active isoform of STAT3) and its potential downstream mediators (Bcl-2, Bcl-xL, c-Myc, cyclin D1, VEGF, cIAP-2, Mcl-1, and survivin) were examined, clinical features were investigated, and relative prognostic factors were analyzed. Positive expression of Bcl-2 was observed in 46.7 % (14/30) of patients, c-Myc in 36.7 % (11/30), and cyclin D1 in 23.3 % (7/30). By univariate analysis, Bcl-2 expression was found to be closely associated with shorter overall survival (OS) and progression-free survival. Bcl-2 and c-Myc positive expression were also found to be a factor that affect time to progression to multiple myeloma. In conclusion, results showed Bcl-2 expression to be a clinically significant prognostic indicator for SPB patients and constitutive activated STAT3 may not be the sole primary regulatory mechanism.