Acid ceramidase (AC) overexpression has been observed in prostate cancer cell lines and primary tumors, and contributes to resistance to chemotherapy and radiation. The consequence of AC overexpression is the ability to convert ceramide, which is often produced as a proapoptotic response to stress, to sphingosine, which can then be converted to the prosurvival molecule sphingosine-1-phosphate. In addition to their ability to metabolize ceramide produced in response to stress, we show here that prostate cancer cell lines overexpressing AC also have increased lysosomal density and increased levels of autophagy. Furthermore, pretreatment with 3-methyladenine restores sensitivity of these cells to treatment with C(6) ceramide. We also observed increased expression of the lysosomal stabilizing protein KIF5B and increased sensitivity to the lysosomotropic agent LCL385. Thus, we conclude that AC overexpression increases autophagy in prostate cancer cells, and that increased autophagy enhances resistance to ceramide.