To develop criteria to distinguish among pyogenic infection, nonpyogenic infection, and neoplastic processes in the spine by means of computed tomography (CT), the authors retrospectively analyzed 17 cases of pyogenic infection (20 sites), 40 cases of neoplastic disease (56 sites), and five cases of granulomatous infection (eight sites). Reliable criteria for pyogenic infection were complete prevertebral soft-tissue involvement, diffuse osteolytic destruction, gas within both bone and soft tissue, and a process centering on an intervertebral disk. Neoplastic disease was characterized by posterior element involvement, partial or absent prevertebral soft-tissue swelling, and osteoblastic alterations. In a limited number of cases, nonpyogenic infection was characterized by focal lytic bone involvement and marginal sclerosis. Blinded testing of these criteria indicated potential for improved diagnostic accuracy in clinical practice.