We investigated 115 testicular and 3 epididymal tumors and 6 cases of the complete androgen insensitivity syndrome (AIS) for the expression of inhibin-alpha, CD99, HEA125, PLAP, and chromogranin, using monoclonal antibodies and standard immunhistochemical techniques. Ihibin-alpha was detected in the neoplastic cells in 27 of 27 primary Leydig cell tumors (LCTs), 1 of 1 metastatic LCT, 6 of 20 Sertoli cell tumors (SCTs), 4 of 5 juvenile granulosa cell tumors (GCTs), and 2 of 5 unclassified sex cord-stromal tumors (USCSTs). Except for 2 choriocarcinomas, the choriocarcinomatous component of 1 mixed germ cell tumor, and a small focus of inhibin-positive syncytiotrophoblast in 1 embryonal carcinoma, inhibin-a immunoreactivity was not present in the neoplastic cells of the 38 remaining testicular germ cell tumors; 11 B-cell and 1 T-cell lymphomas; 1 granulocytic sarcoma; and 1 rhabdomyosarcoma of the testis; 1 adenoma of the rete testis, and 3 adenomatoid tumors of the epididymis. Inhibin-alpha immunoreactivity was present in the Sertoli cells and Leydig cells in 5 testicular hamartomas and in 1 Sertoli cell adenoma in 6 cases of AIS; both Sertoli and Leydig cells were also positive in the extranodular testicular parenchyma present in 2 of these cases. CD99 was detected in 10 of 15 primary LCTs, 1 of 7 SCTs, 3 of 5 JGCTs, and in 1 of 5 USCSTs but was not found in any tumor outside the sex cord-stromal category. HEA125 immunostaining was not detected in sex cord-stromal tumors; however, 3 of 12 seminomas, 3 of 12 embryonal carcinomas, 6 of 8 yolk sac tumors, and 1 of 2 teratomas were HEA125 positive. PLAP was not detected in sex cord-stromal tumors except for 4 of 15 primary LCTs but was present in most germ cell tumors. Chromogranin immunostaining was present in the sex cord-like element in 1 of 5 USCSTs, 1 of 8 YSTs, 1 of 2 teratomas, and in 1 of 1 rete adenoma, and in normal adjacent rete testis. In conclusion, although inhibin-alpha and PLAP, and, to a somewhat lesser extent, CD99 and HEA125 immunostaining are helpful in the differential diagnosis of certain testicular neoplasms that are difficult to distinguish on morphologic grounds, chromogranin is far less helpful in this context.