Objective　To investigate the etiology and diagnostic clues of childhood pleural effusion. Methods Two thousand four hundred and nineteen hospitalized cases of pleural effusion from Jan. 1994 to Jan. 2014 were included and divided into infection group and non-infection group. Then the clinical data were collected. Results There were 1523 males (63.0%) and 896 females with an average age of 6.5±4.0 years old. There were 2353 cases in the infection group and 66 cases in the non-infection group. The incidence of fever in infection group was much higher than that in non-infection group, whereas the incidence of dyspnea and moderate-to-large pleural effusion was lower (all P<0.01). There was a significant difference of age distribution among children with different infectious pleural effusion. In infection group, the paragonimus szechuanensis pleurisy occurred preferentially in children 3-7 years old, the tuberculous pleurisy occurred preferentially in children >7 years old and the purulent pleurisy occurred preferentially in children ≤ 3 years old. The prognosis of infection group was much better than that of non-infection group (P<0.01). Conclusions Infection is the predominant cause of childhood pleural effusion. The differential diagnosis from non-infectious pleural effusion should consider the incidence, clinical manifestations and effusion quantity.