Pathologists are increasingly exposed to prostate biopsies with small atypical foci, requiring differentiation between adenocarcinoma, atypical small acinar proliferation suspicious for malignancy, and a benign diagnosis. We studied the level of agreement for such atypical foci among experts in urologic pathology and all-round reference pathologists of the European Randomized Screening study of Prostate Cancer (ERSPC). For this purpose, we retrieved 20 prostate biopsies with small (most <1 mm) atypical foci. Hematoxylin and eosin-stained slides, including 10 immunostained slides were digitalized for virtual microscopy. The lesional area was not marked. Five experts and 7 ERSPC pathologists examined the cases. Multirater kappa statistics was applied to determine agreement and significant differences between experts and ERSPC pathologists. The kappa value of experts (0.39; confidence interval, 0.29-0.49) was significantly higher than that of ERSPC pathologists (0.21; confidence interval, 0.14-0.27). Full (100%) agreement was reached by the 5 experts for 7 of 20 biopsies. Experts and ERSPC pathologists rendered diagnoses ranging from benign to adenocarcinoma on the same biopsy in 5 and 9 biopsies, respectively. Most of these lesions comprised between 2 and 5 atypical glands. The experts diagnosed adenocarcinoma (49%) more often than the ERSPC pathologists (32%) (P<0.001). As agreement was particularly poor for foci comprising <6 glands, we would encourage pathologists to obtain intercollegial consultation of a specialized pathologist for these lesions before a carcinoma diagnosis, whereas clinicians may consider to perform staging biopsies before engaging on deferred or definite therapy.