Giant cell tumor of bone (GCTB) is a benign tumor with a tendency for local recurrence. GCTB may cause lung metastases, and secondary malignant GCTB is rare. Its histological appearance does not predict local aggressiveness and/or the metastatic potential of the tumor. We aimed to investigate the prognostic value of the Ki-67 proliferative index and p53 protein expression in GCTB in predicting local recurrence, lung metastasis, and malignant transformation. We retrospectively reviewed 42 cases of GCTB. The p53 expression was positive in 20 cases. We used 10% as a cut-off value for p53 expression. In 10 cases, there were local recurrences. Lung metastases were found in three cases and malignant transformation was found in one case with classical GCTB located in the sacrum three years following diagnosis. The Ki-67 index was higher in cases with recurrence, but this difference was not statistically significant. Of the recurrent cases, two had no p53 staining while eight had moderate-to-strong staining. The staining was usually weakly positive in the non-recurrent cases. In conclusion, we believe that p53 may be used as a marker for the biological behavior of GCTB.