Rationale: Smoking induced oxidative stress contributes to COPD, a lung disease characterized by low lung function and increasing mortality worldwide. The counterbalance for this effect may be provided by e.g. increased intake of the antioxidant vitamin C or endogenously acting antioxidant enzymes like glutamate cysteine ligase (GCL) that is responsible for glutathione biosynthesis. Objectives: To investigate associations of functional polymorphisms in GCL subunits (GCLM and GCLC) with lung function level and its longitudinal course, with vitamin C and smoking habits as potential interactive factors. Methods: Two independent general population samples (Doetinchem, n=1,152 and Vlagtwedde-Vlaardingen, n=1,390) with multiple lung function (FEV₁, FVC) measurements were genotyped for three polymorphisms (C(-129)T, C(-588)T, and a trinucleotide GAG repeat (TNR)) in the subunits of GCL. Genetic effects on lung function level and decline were estimated using linear regression and linear mixed effect models adjusted for confounders. Findings were further investigated for interactions with vitamin C intake in the Doetinchem cohort. Main Results: GCLC polymorphisms were significantly associated with lower lung function levels in interaction with packyears smoked in both cohorts. TNR variants in GCLC were associated with accelerated FEV₁ decline in both cohorts in interaction with packyears. All significant effects were specifically present in subjects within the lowest tertile of vitamin C intake. Conclusions: GCLC is a novel susceptibility gene for low level of lung function in two independent populations. We provide suggestive evidence that this occurs due to an interaction between GCLC polymorphisms, smoking, and low vitamin C intake, which all contribute to the oxidative burden.