Little attention has been paid to pneumococcal carriage and disease in Amerindians from Latin America. The Warao people, an indigenous population from Venezuela, live in the delta of the Orinoco River in geographically isolated communities with difficult access to medical care. To obtain insight into pneumococcal carriage and the theoretical coverage of pneumococcal vaccines in this population, we investigated pneumococcal colonization, serotype, and genotype distribution among Warao children in 9 distinct, geographically isolated communities in the Delta Amacuro area in the northeast of Venezuela. From April 2004 through January 2005, a total of 161 Streptococcus pneumoniae isolates were recovered from single nasopharyngeal swab samples obtained from 356 children aged 0-72 months. The overall pneumococcal carriage rate was 49%, ranging from 13% to 76%, depending on the community investigated and the age of the children (50% among children aged <2 years and 25% among children aged >2 years). The most frequent serotypes were 23F (19.5% of isolates), 6A (19.5%), 15B (10.4%), 6B (9.1%), and 19F (7.2%). The theoretical coverage of the 7-valent pneumococcal conjugate vaccine, including the cross-reactive nonvaccine serotype 6A, was 65%. A total of 26% of the isolates were resistant to first-line antibiotics, with 70% of these strains being covered by the 7-valent pneumococcal conjugate vaccine. Restriction fragment end labelling analysis revealed 65 different genotypes, with 125 (80%) of the isolates belonging to 27 different genetic clusters, suggesting a high degree of horizontal spread of pneumococcal strains in and between the villages. The high colonization rates and high (registered) acute respiratory tract infection morbidity and mortality in this part of Venezuela suggest that Warao children are at increased risk for pneumococcal disease and, therefore, benefit from vaccination.