Higher mesothelial cell counts (HM) greater than 5% of total cell counts in tuberculous pleural effusions (TBPE) have been described in human immunodeficiency virus (HIV)-infected patients, however the nature and risk factors in HIV-negative patients with TBPE are unknown. The purpose of the study was to characterize the clinical manifestation of HM in HIV-negative patients with TBPE and evaluate the risk factors of developing HM-TBPE. This retrospective study was undertaken in HIV-negative patients with TBPE from the Far Eastern Memorial Hospital Tuberculosis database. The cytologist and examining specialist differentiated and quantified the cell counts. HM-TBPE was defined when more than 5% of total cell counts in the pleural fluid were mesothelial cells. Multivariate analysis was calculated with stepwise logistic regression for HM-TBPE risk factors. Nineteen patients were diagnosed as HM-TBPE, while 30 were diagnosed with lower mesothelial cell counts TBPE (LM-TBPE). Compared with LM-TBPE patients, those with HM-TBPE had significantly decreased hemoglobin and serum albumin levels (p<0.05). Organ dysfunction such as congestive heart failure, liver cirrhosis and renal failure was significantly more common in patients with HM-TBPE (47.4%) than in patients with LM-TBPE (13.3%; p=0.01). Multivariate analysis revealed that independent risk factors for developing HM-TBPE included hypoalbuminemia (odds ratio =1.6; 95% confidence interval = 1.1–13.8) and the presence of organ dysfunction (odds ratio =4.5; 95% confidence interval = 1.4–17.5). Baseline hypoalbuminemia and comorbidities were independent risk factors for development of HM-TBPE in HIV-negative patients. Mesothelial cell counts should not be used alone in the diagnosis of TBPE. An understanding of the organ dysfunction associated with HM-TBPE in HIV-negative patients could avoid delayed diagnosis and treatment of tuberculosis.