Abstract Background: Variation at TP63 has recently been shown to be associated with lung adenocarcinoma in the Asian population. Methods: To investigate how this finding translates to the European population we compared the genotypes of SNPs annotating the TP63 locus at 3q28 in 4,462 lung cancer patients, including 911 with adenocarcinoma, and 8,235 controls from the United Kingdom. Results: A statistically significant association between adenocarcinoma risk and SNP genotype was shown: rs10937405, OR = 1.21, P = 1.82 × 10−4; rs17429138, OR = 1.23, P = 7.49 × 10−5; and rs4396880, OR = 1.21, P = 2.03 × 10−4. Haplotype analysis was consistent with a single TP63 risk locus defined by SNPs rs10937405, rs17429138, and rs4396880. While no association between SNPs and small cell lung cancer was shown, the rs10937405 and rs439680 associations were significant for squamous cancer (respective P-values, 0.0022 and 0.02). Conclusions: These findings show TP63 variation is a risk factor for the development of lung adenocarcinoma in the UK population. Furthermore, they provide additional insight into the subtype-specificity of the 3q28 lung cancer association. Impact: Our data confirm the association of 3q28 with lung adenocarcinoma and that this association is not confined to the Asian population. Elucidating the functional basis of this association will be contingent on future fine mapping of the TP63 loci. Cancer Epidemiol Biomarkers Prev; 20(7); 1453–62. ©2011 AACR.