This study examined the roles of two different diagnostic approaches to children with fever of unknown origin in determining the patterns of pneumococcal bacteraemia in two Spanish regions by comparing their main epidemiologic characteristics. Whereas a blood culture is routinely obtained in this setting in Navarre, this is not generally the case in Majorca. Additionally, the potential role of antibiotic consumption in each region was also analysed. Cumulative incidences in children under the age of 14 years were 26.6 per 100,000 child-years in Navarre (121.1 in children <2 years of age) and 7.3 per 100,000 child-years in Majorca (33.3 in children <2 years of age). In contrast, the incidences per 1,000 blood cultures were similar in both regions. The relative risks of occult bacteraemia, bacteraemic pneumonia and meningitis among the children of Navarre compared to Majorcan children were 11.8, 2.6 and 0.8, respectively. The risk for less virulent (vaccine serotypes plus 6A, 19A and 23A) and for more virulent serotypes (1 and 7) was 4.9 and 3.1 times higher in Navarre, respectively. The number of 7-valent pneumococcal conjugate vaccine (PCV7) doses administered between 2003 and 2004 were also higher in Navarre. Conversely, antibiotic resistance and paediatric prescriptions for broad-spectrum antibiotics were greater in Majorca. Although the most salient differences between both regions, including the effectiveness of pneumococcal conjugate vaccine in Navarre, appeared to be confounded by the higher frequency of blood cultures taken there, certain differences in serotype composition may be explained by the higher antibiotic consumption in Majorca.