In various medical domains, inhalation of nitrous oxide (N2O) in oxygen (O2) is indicated to alleviate pain and anxiety during routine treatment. Repeat treatment may often be indicated. Little data are available, however, to evaluate the long-term efficacy and side effects of reiterated N2O/O2 sedation. The aim of this study was to compare behavior during dental treatment under a premix of 50% N2O/O2 between first experience and repeat experiences of sedation in a cohort of uncooperative patients. Five hundred forty-three patients (age range, 1-94 years; mean, 17 +/- 16 years) experiencing conscious sedation for dental treatment for the first time were recruited at a special care unit during 3 years. A modified Venham scale was used to evaluate patient behavior at 5 steps during each session. Completion of planned treatment and occurrence of adverse side effects of sedation were additional criteria. Patients experienced sedation for the first time for 378 sessions, and the session was a repeat experience in 843 cases (number of visits: range, 1-6). Patient cooperation significantly improved during visits at first contact with the dentist and when applying the mask (P < 0.0001, between sessions 1 and 2). Between the first and the third sessions, the percentage of very uncooperative patients decreased from 23% to 3.7% at first contact with the dentist and from 22.3% to 8.5% on application of the mask. Experience of reiterated dental treatment under sedation with 50% N2O/O2 premix helps uncooperative patients to cope with dental treatment in the long term.