BACKGROUND: This study evaluates the effectiveness of the target-controlled infusion (TCI) of remifentanil through stepwise increases in the effect-site concentration (Ceff) in preventing coughs. METHODS: In a preliminary study, we randomly selected 140 patients to receive remifentanil through two-step increases in Ceff (1.0 ng/ml to 4.0 ng/ml: Group R1-4; 2.0 ng/ml to 4.0 ng/ml: Group R2-4). Based on the results of the preliminary study, we employed another sample of 140 patients and implemented a three-step increase in TCI (1.0 ng/ml to 2.0 ng/ml to 4.0 ng/ml: Group R1-2-4). We then compared this treatment with direct targeting based on 4.0 ng/ml TCI (Group R4). We recorded the episodes of coughs, rating them as mild (1-2), moderate (3-4), or severe (5 or more). RESULTS: In Group R1-4, one patient (1.5%) coughed during the first step, and five (7.3%) coughed during the second step. In Group R2-4, nine (13.2%) coughed during the first step, but none coughed during the next step. Only one patient had a mild cough during the three-step increase in TCI, that is, patients in Group R1-2-4 were significantly less likely to cough than those in Group R4 (P < 0.001). CONCLUSIONS: Stepwise increases in the TCI of remifentanil reduced the incidence of remifentanil-induced coughing, and the three-step increase in TCI nearly eliminated remifentanil-induced coughing.