Tumor necrosis factor-α (TNF-α) is a pro-inflammatory mediator of the immune response to allogenic and infectious stimuli. Non-immunosuppressed individuals possessing a NcoI restriction enzyme site in the TNF gene locus produce less TNF-α in vitro and in vivo compared with individuals lacking this restriction site. We performed polymerase chain reaction amplification and restriction enzyme fragment length analysis of the TNF locus from 86 liver transplant recipients to determine if presence of the NcoI site is associated with the frequency of rejection or infection, time to rejection or infection, and patient and graft survival. We controlled for recipient primary diagnosis, age, sex, United Network for Organ Sharing status, year of transplant, type of immunosuppression, use of anti-lymphocyte agents, and graft ischemia time. Fifty-six recipients possessed the NcoI+/low TNF-α genotype and 30 were NcoI-/high TNF-α genotype. In the first year after transplant, there were no significant differences in the frequency, or time to first rejections or the overall number of rejection episodes between the two genotypes. NcoI+/low TNF-α genotype recipients had significantly more infections (1.52 vs. 0.87, P=0.014). In a linear regression, multivariate model controlling for all marginally significant variables, the NcoI+/low TNF-α genotype was still associated with significantly more infections (P=0.0031). Patient and graft survival were equal for the two groups. One implication of this study, in individuals genetically predetermined to be low TNF-α producers, is that additional inhibition of TNF-α production by routine immunosuppression may be excessive, rendering these individuals less able to respond to infectious stimuli. These patients may benefit from lower doses or with-drawal of corticosteroids.