Purpose: Allelic variations in the HPC1/RNASEL gene, especially the R462Q single nucleotide polymorphism, have been associated with increased susceptibility to prostate cancer. Prior studies have suggested that HPC1 or R462Q associated tumors present with more aggressive clinical features. We assessed a series of men undergoing radical prostatectomy for clinical and pathological measures of tumor aggressiveness according to the RNASEL R462Q genotype. Materials and Methods: A prospective analysis of 232 men treated for prostate cancer with radical prostatectomy was performed. Disease aggressiveness at diagnosis was assessed by age at disease onset, biopsy Gleason score, clinical T stage and pretreatment prostate specific antigen. Tumor aggressiveness was assessed pathologically by tumor volume, extraprostatic extension, seminal vesicle involvement and lymph node metastasis. Clinical and pathological characteristics were then correlated with RNASEL genotype. Results: Of the 232 men studied 104 (45%) were homozygous WT, 101 (43%) were heterozygous and 27 (12%) were homozygous for the R462Q variant, mirroring the distribution in the general population. No significant differences were seen between genotypes in age at disease onset, pretreatment characteristics or pathological features, as assessed by surgical grade and pathological stage. Tumors homozygous for the R462Q variant were of smaller volume than other genotypes (p = 0.02). Conclusions: This prospective study suggests that prostate cancer in patients with the R462Q allelic variant of the HPC1/RNASEL gene is not associated with more aggressive clinical or pathological features in radical prostatectomy specimens. © 2008 American Urological Association.