A series of linkage studies was previously conducted to identify quantitative trait loci associated with chemically induced lung tumors. However, little is known of genetic susceptibility to spontaneously occurring lung tumorigenesis (SLT) in mice. In this study, we did a whole-genome linkage disequilibrium analysis for susceptibility to SLT in mice using approximately 135,900 single-nucleotide polymorphisms (SNPs) from the Roche and Genomic Institute of the Novartis Research Foundation SNP databases. A common set of 13 mouse strains was used, including 10 resistant strains (129X1/SvJ, AKR/J, C3H/HeJ, C57BL/6J, DBA/2J, NZB/BlnJ, CAST/EiJ, SPRET/EiJ, SM/J, and LP/J) and 3 susceptible strains (A/J, BALB/cJ, and NZW/LaCJ). Fisher exact test was used to assess the association between individual SNPs and susceptibility to SLT. Five regions, SLT1 to SLT5, were mapped on chromosomes 6, 7, 8, 19, and X, respectively. SLT1 to SLT5 showed a significant association with SLT under the empirical threshold (P < or = 0.004) derived from permutation tests. SNP versus SNP association tests indicated that these SLT regions were unlikely to be caused by population substructure. Thus, SLT1 to SLT5 seem to be novel loci controlling the susceptibility to spontaneously occurring lung cancer in mice. Our results provide, for the first time, an insight into the genetic control of spontaneously occurring lung tumorigenesis.