Background: To evaluate the diagnostic utility of alpha-methylacyl CoA racemase (P504S) & HMWCK (34beta E12) in morphologically difficult prostate cancer. Methods: A total of 1034 cases were reviewed and divided into benign (585) malignant (399) and suspicious (50). Immunohistochemistry with HMWCK and AMACR was done on the 50 suspicious cases along with controls. Results: Forty nine suspicious cases were resolved by using both markers where as 1 case was resolved by further support with CD68. The original diagnosis was changed in 15 of 50 (30%) suspicious cases from benign to malignant, one case from benign to high grade PIN and in one case from malignant to benign. Change of diagnosis was seen in 17 of 50 (34%) suspicious cases with a significant p value of 0.002. The overall diagnosis was changed in 17 of 1034 cases (1.64%) of prostatic disease (p < 0.001). Conclusions: A combination of HMWCK and AMACR is of great value in combating the morphologically suspicious cases and significantly increasing the diagnostic accuracy in prostate cancer. Although, in this study the sensitivity and specificity of HMWCK and AMACR were high, yet it should be used with caution, keeping in mind all their pitfalls and limitations.