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Background The Prostate Cancer Prevention Trial (PCPT) demonstrated a 24.8% reduction in the 7-year prevalence of prostate cancer among patients treated with finasteride (5 mg daily) compared with that among patients treated with placebo; however, a 25.5% increase in the prevalence of high-Gleason grade tumors was observed, the clinical significance of which is unknown. One hypothesized explanation for this increase is that finasteride reduced prostate volume, leading to detection of more high-grade tumors due to increased sampling density. This possibility was investigated in an observational reanalysis of the PCPT data, with adjustment for sampling density. Methods A logistic model for the association of high-grade (Gleason score 7-10) prostate cancer with baseline covariates and/or baseline covariates plus prostate volume and number of cores obtained at biopsy was developed using the placebo group (n = 4775) of the PCPT. This model was then applied to the finasteride group (n = 5123) to compare the predicted and observed numbers of high-grade tumors in that group. In a second approach, odds ratios (ORs) for prostate cancer in the finasteride versus placebo groups calculated from binary and polytomous logistic regression models that contained or excluded covariates for gland volume and number of needle cores were compared. Results Median prostate volume was 25% lower in the finasteride group (median = 25.1 [cm.sup.3]) than in the placebo group (median = 33.5 [cm.sup.3]). The logistic model developed in the placebo group showed that the likelihood of detection of high-grade prostate cancer decreased as volume increased (for each 10 [cm.sup.3] increase in prostate volume, OR = 0.81, 95% confidence interval [CI] = 0.74 to 0.90). Based on this model, 239 high-grade prostate cancers were predicted in the finasteride group, whereas 243 were observed, a non-statistically significant difference. Among all participants, the odds ratios for high-grade cancer in the finasteride versus placebo groups decreased from 1.27 (95% CI = 1.05 to 1.54) with adjustment for baseline covariates to 1.03 (95% CI = 0.84 to 1.26) following additional adjustment for gland volume and number of biopsy cores in binary outcome models and from 1.14 (95% CI = 0.94 to 1.38) to 0.88 (95% CI = 0.72 to 1.09) following these adjustments in the polytomous models. Conclusions Although analyses using postrandomization data require cautious interpretation, these results suggest that sampling density bias alone could explain the excess of high-grade cancers among the finasteride-assigned participants in the PCPT.