<i>Background:</i> Heregulins (HRG) are a family of growth factors acting as ligands to HER3, HER4 and HER family signalling. HRG has a concentration-dependent differential growth effect – low levels mitogenic, high levels inhibitory. HRG differentially affects hormone-naïve (inhibitory) and castrate- resistant (proliferative) prostate adenocarcinoma (CaP) cell lines. We postulate that differential HRG expression in CaP will be associated with alteration in tumour growth, development and prognosis. <i>Patients and Methods:</i> HRG expression was assessed in 2 cohorts: cohort 1 of 45 patients with paired hormone-naïve and castrate-resistant samples, and cohort 2 of 357 hormone-naïve samples. Correlations between HRG expression and biochemical relapse and survival were determined. <i>Results:</i> In cohort 1, hormone-naïve samples’ high membranous HRG expression was associated with increased time to relapse (p = 0.036), time to death from relapse (p = 0.002) and overall survival (p = 0.001). Membrane HRG fell significantly in post-relapse specimens. In cohort 2, high membranous HRG was associated with increased time to relapse (p = 0.004) and overall survival (p = 0.044) in patients treated with castration therapy but only with overall survival (p = 0.002) in the full cohort. <i>Conclusion:</i> High HRG expression is associated with improved prognosis in hormone-naïve CaP and a fall in expression occurs at castration escape indicating a protective role against castrate resistance.