Prostate cancer progression can be associated with androgen receptor (AR) mutations acquired following treatment with castration and/or an anti-androgen. Abiraterone, a rationally-designed inhibitor of CYP17A1 recently approved for the treatment of docetaxel-treated castration-resistant prostate cancer (CRPC), is often effective, but requires co-administration with glucocorticoids to curtail side effects. Here we hypothesized that progressive disease on abiraterone may occur secondary to glucocorticoid-induced activation of mutated AR. We found that prednisolone plasma levels in CRPC patients were sufficiently high to activate mutant AR. Mineralocorticoid receptor antagonists, such as spironoloactone and eplerenone that are used to treat side-effects related to mineralocorticoid excess, also bound to and activated signaling through both wild-type and mutant AR. Abiraterone inhibited in vitro proliferation and AR-regulated gene expression of AR-positive prostate cancer cells, which could be explained by AR antagonism in addition to inhibition of steroidogenesis. Interestingly, activation of mutant AR by eplerenone was inhibited by MDV3100, bicalutamide or greater concentrations of abiraterone. Therefore, an increase in abiraterone exposure above this threshold could reverse resistance secondary to activation of AR by residual ligands or co-administered drugs. Together, our findings provide a strong rationale for clinical evaluation of combined CYP17A1 inhibition and AR antagonism.