The current study aimed to verify if the safety and effectiveness of inhalation sedation with 50% nitrous oxide in oxygen (N(2)O/O(2)) is maintained when the premix is administrated by trained general practitioners in their dental surgeries compared to its use in the hospital. Success (completion of planned treatment), cooperation (modified Venham scale), and adverse events were recorded. The acceptability of the technique to the patients, the level of patient cooperation, the ease of use, and the satisfaction of the dentist were also evaluated. Thirty-three general practitioners included 549 patients and recorded 638 sessions of N(2)O/O(2) sedation for dental treatment. Of the sessions, 93.7% were successful in terms of both sedation and treatment. Patient cooperation was seen to improve under N(2)O/O(2) sedation, and for 91% of the sessions, the patients declared that they would like future treatment to be undertaken in the same way. No serious adverse events were recorded. Minor adverse events were noted for 10% of the sessions (behavioural, vagal, and digestive disorders). These results were similar to those found for sessions undertaken in hospital practice. The main difference was in the type of patient treated-more patients received N(2)O/O(2) sedation in general practice for a one-off indication or for dental phobia, and more patients with intellectual disability and more pre-cooperative children were treated in hospital practice. This study gives strong supporting evidence for the safety and effectiveness of inhalation sedation using 50% N(2)O/O(2) in general dental practice for healthy patients.