Prenatal maternal smoking is a risk factor for lower birth weight. We performed epigenome-wide association analyses of placental DNA methylation (DNAm) at 720077 Cytosine-phosphate-Guanine-sites (CpGs) and prenatal maternal smoking among 441 mother-infant pairs (2010-2014) and evaluated if DNAm mediates the association between smoking and birth weight using mediation analysis. Mean (SD) birth weight was 3443 grams (423) and 38 mothers (8.6%) reported smoking at a mean of 9.4 weeks of gestation. Prenatal maternal smoking was associated with a 175-gram lower birth weight (95% CI: -305.5, -44.8) and with differential DNAm of 71 CpGs in placenta robust to latent-factor adjustment reflecting cell-types (Bonferroni-P<6.94x10-8). Of the 71 CpGs, seven mediated the association between prenatal smoking and birth weight (MDS2, PBX1, CYP1A2, VPRBP, WBP1L, CD28 and CDK6 genes) and prenatal smoking by DNAm interactions on birthweight were observed for five CpGs. The strongest mediator, cg22638236, was annotated the PBX1 gene body involved in skeletal patterning and programming with a mediated effect of 301-gram lower birth weight (95% CI: -543, -86) among smokers but no mediated effect for non-smokers (β= -38-gram; 95% CI: -88, 9). Prenatal maternal smoking might interact with placental DNAm at specific loci mediating the association with lower infant birth weight.