Paradoxical response (PR) is the unusual expansion or new formation of a tuberculous lesion during anti-tuberculosis (TB) treatment. Pleural TB is the second most common form of extrapulmonary TB and has clinical importance because it occurs in a restricted space. Limited information is available for PR in HIV-negative patients with pleural TB. The aim of this study was to evaluate the clinical characteristics and risk factors of PR in HIV-negative patients with pleural TB. Patients diagnosed with pleural TB between 2003 and 2008 at Chung-Ang University Hospital and Yong-San Hospital, Seoul, South Korea were included. We evaluated the incidence and treatment outcome of PR in pleural TB, and compared baseline clinical characteristics and laboratory findings between TB patients with PR and those without PR. PR was present in 32 (23%) of 139 patients after mean 51.1 days following initiation of treatment. Out of 32 patients, 18 patients needed additional treatment for symptom control. PR patients had a high incidence of adverse drug reaction such as drug skin reaction or liver function abnormality (P < 0.05). The risk factors for PR are younger age, high serum albumin level, low proportion of lymphocyte, and high proportion of PMN in pleural fluid (P < 0.05). PR is not an uncommon problem in HIV-negative pleural TB and half of these patients need additional treatment. Therefore, physicians must pay more attention for PR during the management of pleural TB in the expected patients to develop PR.