To the workup of metastatic squamous cell carcinoma (SCC) of unknown primary, we studied an immunohistochemical panel including thyroid transcription factor (TTF-1), napsin A, villin, CDX-2, K903, CK5/6, p63, p16, CK7, and CK20. Using tissue microarray, we compared 194 SCC cases from the following sites: 35 lung, 34 skin, 14 cervix, 4 vagina, 16 vulva, 8 penis, 9 anus, 3 rectum, 10 esophagus, 4 bladder/urethra, and 57 SCC from various head and neck sites. p63 and K903 stained positively in 100% of cases, and CK5/6 in nearly 100% of cases, with the exception of 1 lung. CK7 was positive in 31.6% of all cases, with varying positivity according to the site. CK20 was negative in all cases except 1 lung. Napsin A was positive in 25.8% of lung, 7.7% of skin, 37.5% of penis, and 13.3% of tongue, and negative in all other sites. TTF-1 was positive only in 1 lung. p16 positivity ranged from 21.43% in vulva, to 75% in vagina and anus, and it was negative in lung, penis, bladder/urethra, and some head and neck. CDX-2 was negative in all cases except 1 vulva. Villin was negative in all cases. We conclude that immunohistochemistry has very limited value in determining the primary site of metastatic SCC. If lung is in the differential versus head and neck, esophagus, anorectal, or genital SCC, a panel including TTF-1, napsin A and p16 may be helpful, since positive TTF-1 and/or napsin A would favor lung primary, and positive p16 would favor an extrapulmonary site.