Clinical, pathologic, and molecular evidence indicate that bladder cancer is heterogeneous with pathologic/molecular features that define distinct subphenotypes with different prognoses. It is conceivable that specific patterns of genetic susceptibility are associated with particular subphenotypes.To examine evidence for the contribution of germline genetic variation to bladder cancer heterogeneity.The Spanish Bladder Cancer/EPICURO Study is a case-control study based in 18 hospitals located in five areas in Spain. Cases were patients with a newly diagnosed, histologically confirmed, urothelial cell carcinoma of the bladder from 1998 to 2001. Case diagnoses were reviewed and uniformly classified by pathologists following the World Health Organisation/International Society of Urological Pathology 1999 criteria. Controls were hospital-matched patients (n=1149).A total of 1526 candidate variants in 423 candidate genes were analysed. Three distinct subphenotypes were defined according to stage and grade: low-grade nonmuscle invasive (n=586), high-grade nonmuscle invasive (n=219), and muscle invasive (n=246). The association between each variant and subphenotype was assessed by polytomous risk models adjusting for potential confounders. Heterogeneity in genetic susceptibility among subphenotypes was also tested.Two established bladder cancer susceptibility genotypes, NAT2 slow-acetylation and GSTM1-null, exhibited similar associations among the subphenotypes, as did VEGF-rs25648, which was previously identified in our study. Other variants conferred risks for specific tumour subphenotypes such as PMS2-rs6463524 and CD4-rs3213427 (respective heterogeneity p values of 0.006 and 0.004), which were associated with muscle-invasive tumours (per-allele odds ratios [95% confidence interval] of 0.56 [0.41-0.77] and 0.71 [0.57-0.88], respectively) but not with non-muscle-invasive tumours. Heterogeneity p values were not robust in multiple testing according to their false-discovery rate.These exploratory analyses suggest that genetic susceptibility loci might be related to the molecular/pathologic diversity of bladder cancer. Validation through large-scale replication studies and the study of additional genes and single nucleotide polymorphisms are required.