AbstractPurpose: Matrix metalloproteinases (MMP) promote tumor invasion and alter microenvironment. MMP levels are elevated in bladder cancer patients correlating with more advanced stage. We tested whether polymorphisms in MMP genes modify the risk of bladder cancer invasiveness and whether smoke exposure modifies this risk.Experimental Design: Using a case-only study, we examined the association of 11 single-nucleotide polymorphisms and one microsatellite polymorphism in MMP genes MMP1, MMP2, MMP3, MMP8, MMP9, and MMP12 with the risk of invasive bladder cancer in 243 Caucasian patients with muscle invasive compared with 315 Caucasian patients with superficial disease.Results: The MMP9 microsatellite ≥24 CA repeat and MMP12 −82 G alleles were associated with a higher risk of bladder cancer invasiveness [odds ratio (OR), 3.10; 95% confidence interval (95% CI) 1.17-8.23 and OR, 1.50; 95% CI, 1.00-2.28, respectively]. Ever smokers with the MMP9 ≥24 CA repeat allele had a 5.16-fold (95% CI, 1.56-17.1) increased risk of invasiveness compared with wild-type never smokers. Ever smokers with the MMP12 G allele also had an increased risk of bladder cancer invasiveness (OR, 2.32; 95% CI, 1.30-4.12).Conclusions: Our results suggest that genetic changes in MMPs are associated with the development of invasive bladder cancer.