The plasminogen pathway plays an important role in the behavior of many tumors including lung cancer. Hence genetic variants encoding plasminogen activator (PLAU), plasminogen receptor (PLAUR), plasminogen activator inhibitor 1 (PAI-1) and plasminogen activator inhibitor 2 (PAI-2) may contribute to lung cancer prognosis. To investigate this proposition we genotyped PAI-1 A15T, PLAU L141P, PLAUR L317P and PAI-2 S413C variants in 698 patients with lung cancer, 522 with non-small cell (NSCLC) and 176 with small cell lung cancer (SCLC). PAI-1 A15T was significantly associated with overall survival (OS), with carriers of variant alleles having a worse prognosis (hazard ratio (HR)=1.14; 95% confidence interval [CI]: 1.03-1.26). An association was also detected between OS in NSCLC and carrier status for PAI-2 413C (HR=1.13; 95% CI: 1.01-1.24). These common genetic variants identified warrant further evaluation as promising prognostic markers of patient outcome.