Bipolar disorder (BD) is associated with an increased risk of tobacco dependence, the leading addictive substance worldwide. Toll-like receptor 4, a sensor of pathogens and of products of cellular stress and damage, is a major innate immune molecule and logical candidate gene for tobacco dependence in BD because (i) the involvement of TLR4 molecules in several substance use disorders has been suggested, (ii) and the association between the TLR4 gene and BD. We analysed herein the potential association between six TLR4 polymorphisms and lifetime tobacco smoking in 514 BD patients. Significant association between tobacco smoking and rs10759932 was found (genotype, Cochrane Armitage trend test, p = 0.008, p(corrected) = 0.040 and alleles, p = 0.008; p(corrected) = 0.040), where the C minor allele is associated with a protective effect, even after adjusting for confounding factors (OR = 1.54 [1.04-2.30], p = 0.03). Our results suggest that TLR4 gene polymorphism may act as an intermediate factor for the association between tobacco smoking addiction and BD. (C) 2017 Elsevier B.V. All rights reserved.