There is currently no standard therapy for patients with prostate cancer who have progressive rise in PSA levels despite treatment with hormonal ablation and antiandrogen withdrawal (stage D0.5). One potential treatment option is the use of a different androgen receptor antagonist (ARA), such as nilutamide. We report a case of a 66-year-old gentleman with greater than a 46 month sustained response to nilutamide therapy after failing bicalutamide therapy and its subsequent withdrawal. The patient continues to have undetectable PSA levels and an excellent performance status. This case demonstrates the prolonged response to a second-line ARA in patients deemed to have androgen insensitive prostate cancer. Further investigation of the potential role of nilutamide therapy as second-line antiandrogen therapy is warranted as monotherapy and/or in combination with other promising novel approaches including PSA-based vaccines.