BACKGROUND: Although fever is part of the normal inflammatory process after immunisation, prophylactic antipyretic drugs are sometimes recommended to allay concerns of high fever and febrile convulsion. We assessed the effect of prophylactic administration of paracetamol at vaccination on infant febrile reaction rates and vaccine responses. METHODS: In two consecutive (primary and booster) randomised, controlled, open-label vaccination studies, 459 healthy infants were enrolled from ten centres in the Czech Republic. Infants were randomly assigned with a computer-generated randomisation list to receive three prophylactic paracetamol doses every 6-8 h in the first 24 h (n=226) or no prophylactic paracetamol (n=233) after each vaccination with a ten-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) co-administered with the hexavalent diphtheria-tetanus-3-component acellular pertussis-hepatitis B-inactivated poliovirus types 1, 2, and 3-H influenzae type b (DTPa-HBV-IPV/Hib) and oral human rotavirus vaccines. The primary objective in both studies was the reduction in febrile reactions of 38.0 degrees C or greater in the total vaccinated cohort. The second objective was assessment of immunogenicity in the according-to-protocol cohort. These studies are registered with ClinicalTrials.gov, numbers NCT00370318 and NCT00496015. FINDINGS: Fever greater than 39.5 degrees C was uncommon in both groups (after primary: one of 226 participants [<1%] in prophylactic paracetamol group vs three of 233 [1%] in no prophylactic paracetamol group; after booster: three of 178 [2%] vs two of 172 [1%]). The percentage of children with temperature of 38 degrees C or greater after at least one dose was significantly lower in the prophylactic paracetamol group (94/226 [42%] after primary vaccination and 64/178 [36%] after booster vaccination) than in the no prophylactic paracetamol group (154/233 [66%] after primary vaccination and 100/172 [58%] after booster vaccination). Antibody geometric mean concentrations (GMCs) were significantly lower in the prophylactic paracetamol group than in the no prophylactic paracetamol group after primary vaccination for all ten pneumococcal vaccine serotypes, protein D, antipolyribosyl-ribitol phosphate, antidiphtheria, antitetanus, and antipertactin. After boosting, lower antibody GMCs persisted in the prophylactic paracetamol group for antitetanus, protein D, and all pneumococcal serotypes apart from 19F. INTERPRETATION: Although febrile reactions significantly decreased, prophylactic administration of antipyretic drugs at the time of vaccination should not be routinely recommended since antibody responses to several vaccine antigens were reduced. FUNDING: GlaxoSmithKline Biologicals (Belgium).