Introduction Glutathione S-transferase pi 1 metabolizes carcinogens from tobacco smoke in the lung. We tested whether genetically altered glutathione S-transferase pi 1 activity affects lung function and risk for tobacco-related cancer and mortality in the general population. Methods We genotyped 66,069 individuals from the white general population for two common functional variants in the glutathione S-transferase pi 1 gene (GSTP1)—amino acid isoleucine 105 changed to a valine (Ile105Val) and amino acid alanine 114 changed to a valine (Ala114Val)—and recorded lung function, lung cancer, tobacco-related cancer, and death as outcomes. Results Lung function was increased stepwise with the Ile105Val genotype overall (p < 0.01) and among smokers separately (p < 0.01). Adjusted hazard ratios for lung cancer, tobacco-related cancer, and death were reduced stepwise with the Ile105Val genotype (p < 0.02): Ile105Val homozygotes and heterozygotes versus noncarriers had hazard ratios for lung cancer of 0.64 (0.47–0.89) and 0.93 (0.78–1.11), for tobacco-related cancer of 0.74 (0.60–0.92) and 0.92 (0.81–1.04), and hazard ratios for death of 0.87 (0.80–0.95) and 0.94 (0.89–0.99), respectively. Population prevented fractions of lung cancer, tobacco-related cancer, and death due to Ile105Val homozygosity were 4%, 3% and 2%, respectively. The Ala114Val genotype was associated with reduced mortality (p < 0.01) but not with lung function, lung cancer, or tobacco-related cancer. Conclusion GSTP1 Ile105Val was associated with increased lung function, reduced risk for lung cancer and tobacco-related cancer, and reduced all-cause mortality in the general population.