Objective: To assess the effect of eligibility criteria on exclusion rates, generalizability and outcome heterogeneity in ALS clinical trials, and to assess the value of a risk-based inclusion criterion. Methods: A literature search was performed to summarize eligibility criteria of clinical trials. The extracted criteria were applied to an incidence cohort of 2,904 consecutive ALS patients to quantify their effects on generalizability and outcome heterogeneity. We evaluated the effect of a risk-based selection approach on trial design using a personalized survival prediction model. Results: We identified 38 trials: enrolled patients reveal a large variability between trials of all patient characteristics (p < 0.001), except for the proportion of males (p = 0.21). Exclusion rates varied widely (from 14% to 95%; mean 59.8% (95% CI 52.6-66.7)). Stratification of the eligible populations into prognostic subgroups showed that eligibility criteria lead to exclusion of patients in all prognostic groups. Eligibility criteria neither reduce heterogeneity in survival time (from 22.0 to 20.5 months, p = 0.09) nor affect between-patient variability in functional decline (from 0.62 to 0.65, p = 0.25). In none of the 38 trials were the eligibility criteria found to be more efficient than the prediction model in optimizing sample size and eligibility rate. Conclusions: The majority of ALS patients are excluded from trial participation, which questions the generalizability of trial results. Importantly, eligibility criteria only minimally improve homogeneity in trial endpoints. An individualized risk-based criterion could be used to balance the gains in trial design and loss in generalizability.