Objective: Metals have been suggested as risk factors for amyotrophic lateral sclerosis (ALS), but only retrospective studies are available to date. We compared metal levels in prospectively collected blood samples from ALS patients and controls to investigate whether metals are associated with ALS mortality. Methods: A nested ALS case-control study was conducted within the prospective EPIC cohort. Cases were identified using death certificates. We analyzed metal levels in erythrocyte samples obtained at recruitment as a biomarker for metal exposure from any source. Concentrations of arsenic, cadmium, copper, lead, manganese, mercury, selenium, and zinc were measured by inductively coupled plasma-mass spectrometry. To estimate ALS risk, we applied conditional logistic regression models. Results: The study population comprised 107 cases (65% female) and 319 controls matched for age, sex, and study center. The median time between blood collection and death from ALS was 8 years (range 1–15). Comparing the highest with the lowest tertile, cadmium (odds ratio (OR) 2.04, 95% confidence interval (CI) 1.08–3.87) and lead (OR 1.89, 95% CI 0.97–3.67) concentrations suggest associations with increased ALS risk. Zinc was associated with a decreased risk (OR 0.50, 95% CI 0.27–0.94). Associations for cadmium and lead remained when analyses were limited to non-current smokers. Interpretation: This is the first study to compare metal levels prior to disease onset, minimizing reverse causation. The observed associations suggest that cadmium, lead, and zinc may play a role in the etiology of ALS. Cadmium and lead may act as intermediaries in the pathway from smoking to ALS.