Cystic change in adenocarcinoma of the prostate is unusual and may be confused with benign cystic atrophy. Limited data exist on the pathologic attributes of microcystic change in malignant prostatic glands. The aim of this study was to assess histologic and immunohistologic characteristics of microcystic adenocarcinoma of the prostate. This alteration was defined as cystic dilatation and rounded expansion of the malignant gland profile, with a flat luminal cell lining layer. We identified 53 cases with microcystic change from a survey of 472 radical prostatectomy cases, for an incidence of 11.2%. The greatest diameter of the dilated cancer glands was 0.4 to 0.9 mm, with a mean diameter 10-fold greater than adjacent small malignant glands. The microcystic glands were typically adjacent to usual small acinar adenocarcinoma. Atrophic features were seen at least focally in all cases, although many microcystic adenocarcinoma epithelia exhibited a moderate amount of cytoplasm. Gleason grade 3 was the predominant grade of the adjacent nonmicrocystic malignant glands. Intraluminal crystalloids, and wispy blue intraluminal mucin were seen in all cases. Ninety-six percent of the microcystic cases showed alpha-methylacyl CoA racemase overexpression and all cases showed complete basal cell loss (using 34betaE12 and p63 antibodies) in immunohistochemistry. Microcystic adenocarcinoma of the prostate is a distinctive histomorphologic presentation of prostatic adenocarcinoma that is deceptively benign-looking at low magnifications. Detection of intraluminal crystalloids or wispy blue mucin at low magnification, immunostains for alpha-methylacyl CoA racemase, and basal cells, and a search for adjacent usual small acinar adenocarcinoma are helpful diagnostic aids. Diagnostic awareness of this growth pattern of prostatic carcinoma is important to avoid underdiagnosis of adenocarcinoma of the prostate.