Many prostate cancer (PCa) patients die of recurrent disease due to the emergence of hormone-independent cancer cells of which the mechanism is not fully understood. Our previous studies demonstrated that most castration- resistant prostate cancers (CRPC) overexpress the HOXB13 transcription factor to confer positive growth signals. Since HOXB13 also suppresses p21WAF1/CIP1 (p21) expression, we studied the correlation between HOXB13 and p21 in selected samples of PCa. While there was no statistically significant correlation between expression of HOXB13 and p21, HOXB13-deficient tumors had three times higher odds for expressing p21 than HOXB13-positive tumors. Moreover, CRPC showed more negative correlation than hormone-dependent PCa (HDPC). Further in vitro proliferation assay demonstrated that androgen did not affect the growth-suppressive function of p21 in androgen-dependent PCa cells, suggesting that p21 seems to override the growth-promoting function of androgen and suppression of p21 expression by HOXB13 is an important step in PCa cell survival under no androgen influence. HOXB13 also inhibited AP-1 signals via suppressed expression of JNK/c-Jun. While HOXB13 suppressed p21 expression via regulation of JNK signals, alteration of p21 expression also affected c-Jun and AP-1 activity. Taken together, overexpression of HOXB13 in CRPC is an important step in avoiding the growth-suppressive effect of p21 in a harsh condition such as an androgen-deprived environment.