The pathogenesis of amyotrophic lateral sclerosis (ALS) is considered to be multifactorial. Several epidemiological studies showed a lower incidence of ALS in women than in men. This suggests a possible protective effect of female reproductive hormones. The aim of this study was to investigate the association between female reproductive hormones and ALS. We performed a population-based, case-control study in the Netherlands between 1st January 2006 and 1st December 2009. Only women with a natural menopause were included in the analysis. A total of 209 (85 %) of 246 female patients and 672 (93 %) of 719 controls returned a questionnaire on reproductive history to calculate the reproductive time-span and lifetime endogenous estrogen exposure (calculated by subtracting the duration of pregnancies and of oral contraceptive use, and the number of post-ovulatory weeks from the reproductive time-span). 131 (63 %) patients and 430 (64 %) age-matched, population-based controls had experienced a natural menopause. Multivariate analysis showed that increasing the reproductive time-span by a year decreases the risk of ALS with an OR of 0.95 (p = 0.005). Each year longer reproductive time-span [HR 0.90 (p = 0.01)] and lifetime endogenous estrogen exposure [HR 0.96 (p = 0.025)] were associated with a longer survival of ALS patients. The positive association of a longer reproductive time-span and susceptibility and survival of ALS might imply that longer exposure to female reproductive hormones has a neuroprotective effect on motor neurons.