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Purpose: Recent studies highlight the role of autophagy in cancer tumorigenesis, recurrence, metastasis, and chemoresistance. p62 is an adapter protein that is crucial for the autophagy pathway. In this study, we will describe the expression of p62 and its correlation with clinic prognosis in osteosarcoma. Methods: Western blot was used to test the expression of p62 in osteosarcoma cell lines (U2OS, KHOS, MG63, Saos-2, U2OSR2, KHOSR2, and 143B). A tissue microarray (TMA) was analyzed by immunohistochemistry to determine the expression levels of p62 in osteosarcoma patients and evaluate any correlation between p62 and clinical characteristics in osteosarcoma patients. Results: p62 was expressed differently in all cell lines. The TMA also showed differential expression in osteosarcoma tissues. Seventy-five of 79 (94.9%) patient tissues exhibited p62 immunostaining, ranging from no staining (4 of 97, 5.1%) to 1+ staining (40 of 79, 50.6%), 2+ staining (17 of 79, 21.5%), and 3+ staining (18 of 79, 22.8%). The low staining (1+) was classified as the p62 weak group (50.6%), the medium staining (2+) and intense staining (3+) were classified as the p62 strong group (44.3%). Analyzing the clinical data of the osteosarcoma TMA, we found that the 5-year survival rate of patients with weak p62 expression was significantly lower than that of the patients with strong p62 expression (p = 0.0165). Furthermore, the decreased p62 expression may be associated with higher metastatic and chemoresistant rates in osteosarcoma patients. Conclusion: Our results suggest that p62 may be an effective predictor of prognosis and a potential target for therapy in osteosarcoma. [ABSTRACT FROM AUTHOR]