The purpose of this study was to examine the relationship between preterm birt h and 22 single nucleotide polymorphisms in genes that encode cytokines and medi ators of apoptosis and host defense. Two hundred two white women with a spontane ous preterm birth of < 35 weeks of gestation were compared with 185 white women with term births. Genotyping was performed with polymerase chain reaction and se quence specific primers. Multivariable analyses included demographic and genetic vari-ables. Alcohol (multivariable odds ratio, 2.3; P =.001] and substance use (multivariable odds ratio, 3.7; P =.01) were associated with preterm birth at < 35 weeks of gestation. Smoking (multivariable odds ratio, 2.3; P =.03), haploty pes IL10 -1082A/-819T/-592A (multivariable odds ratio, 2.1; P =.04), tumor ne crosis factor (TNF)+488A/-238G/-308G (multivariable odds ratio, 2.4; P =.04), and IL4 -509C/C (multivariable odds ratio, 3.4; P =.02), and the presence of M BL2 codon 54Asp (multivariable odds ratio, 2.3; P =.02) were associated independ ently with preterm birth at < 29 weeks of gestation. Homozygosity for IL10 -108 2G/-819C/-592C haplotype (multivariable odds ratio, 1.9; P =.02) was more comm on in women with preterm premature rupture of membranes. Polymorphisms in immuno regulatory genes may influence susceptibility to preterm birth or premature rupt ure of membranes. The purpose of this study was to examine the relationship between preterm birt h and 22 single nucleotide polymorphisms in genes that encode cytokines and medi ators of apoptosis and host defense. Two hundred two white women with a spontaneous preterm birth of <35 weeks of gestation were compared with 185 white women with term births. Genotyping was performed with polymerase chain reaction and se quence specific primers. Multivariable analyzes included demographic and genetic vari-ables. Alcohol (multivariable odds ratio, 2.3; P = .001] and substance use Smoking (multivariable odds ratio, 2.3; P = .03), haploty pes IL10 -1082A / -819T / -592A (multivariable odds ratio, 3.7; P = .01) were associated with preterm birth at <35 weeks of gestation. odds ratio, 2.1; P = .04), tumor ne crosis factor (TNF) + 488A / -238G / -308G (multivariable odds ratio, 2.4; 3.4; P = .02), and the presence of M BL2 codon 54Asp (multivariable odds ratio, Homozygosity for IL10 -108 2G / -819C / -592C haplotype (multivariable odds ratio, 1.9; P = .02) was more comm on in women with preterm premature rupture of membranes. Polymorphisms in immuno regulatory genes may influence susceptibility to preterm birth or premature rupt ure of membranes.