HTLV-1 is the etiologic agent of ATL and HAM/TSP. The majority of HTLV-1-infected individuals remain asymptomatic, indicating that the infection alone is not sufficient to cause the diseases. It has been reported that cytokine gene polymorphisms, including polymorphisms at IL-6 and IL-10 gene, might be important. We analyzed SNP in the promoter region of the IL-6: -174, -572, -597, and -634 positions, and IL-10: -592 position to evaluate the role of these polymorphisms in the HAM/TSP pathogenesis in 133 HTLV-1 infected individuals and in 100 healthy individuals from Salvador, Bahia, Brazil. The -634C allele frequencies were higher among HAM/TSP patients (21.2%) than among oligosymptomatic (6.5%; P = 0.038) and asymptomatic (9.5%; P = 0.025) subjects. Similarly, the -174G allele frequencies were higher in HAM/TSP patients than in oligosymptomatic patients (P = 0.02). Moreover, the -634GC/-174GG genotype combination was identified at a higher frequency (38.5%) in the HAM/TSP patients than in subjects with other clinical status (8.7%; P = 0.016 for oligosymptomatic and 15.5%, P = 0.012 for asymptomatic patients). However, the multivariate logistic regression including the genotypes of the three studied loci showed that only -634 C IL-6 carriers remain as significant and independent TSP/HAM predictor (odds ratio [OR] = 5.31; 95% [CI] = 1.60-17.56; P = 0.006). We suggest that -634 G C in IL-6 could contribute to HAM/TSP development and that identification of the collective influence of several cytokine polymorphisms, their prevalence, and their interaction could help to better understand this disease.