We studied 222 skin biopsies of mycosis fungoides and Sézary syndrome (cutaneous T-cell lymphoma [CTCL]) to document the huge histologic spectrum and to evaluate the earliest histologic changes. Our results indicate that CTCL produces practically all of the patterns used for diagnosing inflammatory skin disease: superficial or superficial and deep perivascular without epidermal changes; spongiotic; psoriasiform, with or without a lichenoid infiltrate; interface, including lichenoid without vacuolar alteration, lichenoid with vacuolar alteration, and vacuolar alteration without a lichenoid infiltrate; follicular, with or without mucin; nodular and diffuse; vasculitis; vesicular; and panniculitis. Unusual examples resembling granuloma annulare, gyrate erythema, lichen planus, and pityriasis lichenoides were seen. To further document the spectrum within each pattern, we analyzed many variables, such as lymphocytic atypia, epidermotropism, epidermal contour, and composition of the dermal infiltrate. Common clues to the diagnosis of CTCL include epitheliotropism with little spongiosis; lymphocytes lined up along the basal layer; hyperconvoluted lymphocytes; and broad areas of slight hyperorthokeratosis that is compact or laminated, with subtle interspersed parakeratosis. Less common clues include Pautrier's microabscesses; granulomatous foci; coexistence of plasma cells and eosinophils; and rounded, hyperplastic rete ridges adjacent to flattened rete. The earliest changes of CTCL appear to be a sparse, superficial perivascular infiltrate with slight or no epidermal hyperplasia and with rare lymphocytes in the lower epidermis, especially the basal layer, often with hyperconvoluted nuclei. Our findings support the hypothesis that CTCL develops sui generis, rather than from another chronic dermatosis.