The skin biopsy is the most useful test for diagnosing leprosy as it allows direct visualization of the Mycobacterium leprae bacteria within nerve and skin tissue. Histopathological examination reveals specific features such as granulomas and acid-fast bacilli, confirming the diagnosis. This test also helps classify the disease type (tuberculoid or lepromatous), guiding appropriate treatment. Other tests like blood culture or imaging do not detect the organism reliably. Thus, a skin biopsy provides definitive evidence of leprosy infection.

Reference: Harrison's Principles of Internal Medicine, J. Larry Jameson et al., 20th Edition.