OBJECTIVE: We examined whether riluzole treatment modifies the associations between the dietary glycemic index (GI) and load (GL) and disease progression in amyotrophic lateral sclerosis (ALS). METHODS: Sporadic ALS patients in the Multicenter Cohort Study of Oxidative Stress who completed a baseline food frequency questionnaire were included (n = 304). Interactions between baseline riluzole treatment and GI/GL on functional decline and tracheostomy-free survival were examined using linear regression and Cox proportional hazard models adjusted for covariates. Age, sex, disease duration, diagnostic certainty, body mass index, bulbar onset, revised ALS functional rating scale (ALSFRS-r) total score, and forced vital capacity, from baseline were included as covariates. RESULTS: Baseline higher GI and GL were associated with less decline of ALSFRS-r total score at 3-month follow-up in the riluzole treatment group (RTG) but not in the no-riluzole group (NRG). When quartile groups were used, GI second [β = -1.9, 95% CI (-4.1, -0.2), p = 0.07], third [β = -3.0, 95% CI (-5.1, -0.8), p <
0.01] and fourth [β = -2.2, 95% CI (-4.3, -0.01), p <
0.05] quartile groups were associated with less ALSFRS-r decline at 3-months compared to the first quartile group (GI <
47.2) among the RTG. Similarly, GL fourth quartile group (GL >
109.5) was associated with less ALSFRS-r decline at 3 months compared to the first quartile group [β = -2.6, 95% CI (-4.7, -0.5), p <
0.05] among the RTG. In NRG, no statistically significant differences in ALSFRS-r decline were found among GI/GL quartile groups. INTERPRETATION: High dietary GI and GL are associated with a slower functional decline only among ALS patients taking riluzole.