The biological behavior of a prostate cancer can be predicted to some degree by the volume and extent (stage) of the tumor, and its histological grade. The deoxyribonucleic acid (DNA) ploidy status has been reported by some to be another independent prognostic factor for localized prostate cancer. We determined the DNA ploidy value of each individual focus of cancer in radical prostatectomy specimens using nuclear image analysis (CAS 200 system). Ploidy results were correlated with the volume, Gleason grade and zone of origin (transition zone or peripheral zone) of each tumor, and with the presence of extracapsular extension or seminal vesicle invasion. There were 141 separate cancers in 68 patients (mean 2.1 per prostate): 9 clinical stage A1, 22 stage A2, 23 stage B1 and 14 stage B2. DNA ploidy correlated significantly (p < 0.0001) with volume, grade, extraprostatic spread and zone of origin. Remarkably, some small cancers (1 cc or less) were nondiploid (3 as small as 0.03 cc). Overall, 15% of cancers 0.01 to 0.1 cc and 31% of those 0.11 to 1.0 cc in volume were nondiploid. Of 101 cancers confined to the prostate 76% were diploid, compared to only 13% of those with extraprostatic spread. Most cancers of transition zone origin (86%) were diploid, compared to only 49% of peripheral zone cancers, and ploidy and volume relationships were significantly different for peripheral zone cancers compared to transition zone cancers. All small nondiploid cancers arose in the peripheral zone, while in the transition zone the smallest nondiploid cancer was 1.17 cc. We conclude that prostate cancers that are nondiploid are highly likely to have adverse pathological features. Some small prostate cancers contain a nondiploid cell population and these cancers arise predominantly within the peripheral zone of the prostate. Ploidy and volume relationships provide further support for the hypothesis that there is a difference in malignant potential between cancers of peripheral zone and transition zone origin.