Narcolepsy is a chronic sleep disorder characterized mainly by excessive daytime sleepiness (EDS) and cataplexy in the case of narcolepsy type 1 (NT1). Pitolisant is a histamine 3 receptor antagonist/inverse agonist that reduces EDS and cataplexy in patients with narcolepsy. We performed a prospective 5-year follow-up, non-interventional study of adults with NT1 and NT2 receiving pitolisant. The primary objectives were to collect information on the long-term safety of pitolisant and analyze the utilization patterns of pitolisant. The secondary objectives were to assess clinical benefit, adherence, impact on patients' quality of life, disease burden, and patient satisfaction. We reported the results of an interim analysis after 42.6 months. The population comprised 370 patients (mean age, 40 ± 15 years; 51.4 % women; NT1, 71.4 %; NT2, 28.6 %); 364 received ≥1 dose of pitolisant. Data were available for 356 patients (97.8 %). Most patients (68.4 %) had ≥1 comorbidity (obesity [BMI≥30], 31.9 %; neuropsychiatric, 31 %; and cardiovascular, 22.8 %). Forty-eight patients (13.2 %) had received no prior narcoleptic treatment, while 98 (31 %) were taking a previous therapy, which was switched to pitolisant. Treatment was combined with pitolisant in 218 (69 %) patients. Pitolisant was discontinued by 131 patients (35.4 %), mainly for safety reasons (14.3 %), lack of response (8.7 %), and patient decision (7.6 %). Overall, 355 treatment-emergent adverse events (3 serious) were reported by 156 patients (42.9 % of safety population), with 218 possibly treatment-related (61.4 %) in 109 patients (29.9 %). Improvements were observed in EDS, cataplexy, and quality of life. Pitolisant was generally safe and well tolerated in patients with NT1 and NT2 and can be used in both types. Improvements were found in EDS, cataplexy, and quality of life, with good adherence and satisfaction.