ABSTRACT: BACKGROUND: Neurofibromatosis 1 (NF-1), a common autosomal dominant disorder, was shown in one study to be associated with a 15-year decrease in life expectancy. However, data on mortality in NF-1 are limited. Our aim was to evaluate mortality in a large retrospective cohort of NF-1 patients seen in France between 1980 and 2006. METHODS: Consecutive NF-1 patients referred to the National French Referral Center for Neurofibromatoses were included. The standardized mortality ratio (SMR) with its 95% confidence interval (CI) was calculated as the ratio of observed over expected numbers of deaths. We studied factors associated with death and causes of death. RESULTS: Between 1980 and 2006, 1895 NF-1 patients were seen. Median follow-up was 6.8 years (range, 0.4-20.6). Vital status was available for 1226 (65%) patients, of whom 1159 (94.5%) survived and 67 (5.5%) died. Overall mortality was significantly increased in the NF-1 cohort (SMR, 2.02; CI, 1.6-2.6; P<10-4). The excess mortality occurred among patients aged 10 to 20 years (SMR, 5.2; CI, 2.6-9.3; P<10-4) and 20 to 40 years (SMR, 4.1; 2.8-5.8; P<10-4). Significant excess mortality was found in both males and females. In the 10-20 year age group, females had a non significant increase in mortality compared to males (SMR, 12.6; CI, 5.7-23.9; and SMR, 1.8; CI, 0.2-6.4; respectively). The cause of death was available for 58 (86.6 %) patients; malignant nerve sheath tumor was the main cause of death (60%). CONCLUSIONS: We found significantly increased SMRs indicating excess mortality in NF1 patients compared to the general population. The definitive diagnosis of NF-1 in all patients is a strength of our study, and the high rate of death related to malignant transformation is consistent with previous work. The retrospective design and hospital-based recruitment are limitations of our study. Mortality was significantly increased in NF-1 patients aged 10 to 40 years and tended to be higher in females than in males.