Background: Genetic susceptibility has a major role in the pathogenesis of acute otitis media (AOM). In the present study, we investigated the variability of 5 cytokine genotypes as related to susceptibility and outcome of AOM in early infancy. Methods: Single nucleotide polymorphisms in IL-6 (-174 GC), IL-10 (-592 CA, -819 CT and -1082 GA), TNF- (-308 GA), IFN- (+874 AT) and TGF-1 (codon 10 CT; codon 25 GC) genes were investigated and related to clinical course and outcome in 96 infants younger than 9 months with AOM. Results: Compared with wild genotypes, IL-10 (-592, -819 and -1082) and TGF-1 (codon 10) genotypes carrying the alternative allele were related to more AOM episodes (P < 0.0001, P < 0.0001, P < 0.0001 and P = 0.002, respectively) and the need for tympanostomy tubes. Furthermore, IL-10 (-1082) and TGF-1 (codon 10) genotypes carrying the alternative allele were related to later onset of first AOM episode than wild-type genotypes (P = 0.007 and P = 0.039, respectively). No relationship was found about AOM complications. Conclusions: Our findings suggest that IL-10 and TGF-1 genotypes are related to the age of AOM onset, multiple AOM episodes and insertion of tympanostomy tubes, pointing to the involvement of anti-inflammatory cytokines in AOM during infancy.