Background: Local and minor systemic adverse events are frequently seen after routine immunisation with diphtheria–pertussis–tetanus. Antipyretics are frequently prescribed for these events and prophylactic administration of acetaminophen is occasionally recommended.

Objective: To determine whether prophylactic administration of acetaminophen has any effect in reducing the incidence of post-vaccination side-effects.

Design: A prospective, comparative trial with telephone interview-based outcome assessment.

Setting: OPD and immunisation room of a tertiary-care paediatric hospital.

Subjects and Methods: 167 children aged between 1·5 and 24 months presenting for routine immunisation were enrolled and allocated to the ‘immediate’ or ‘as-needed’ group. The immediate group had received acetaminophen syrup (10–15 mg/kg, single dose) immediately after vaccination (n = 89); children in the as-needed group were not given prophylactic acetaminophen (n = 78). Parents of both groups were free to give further doses of acetaminophen for fever, pain or irritability. The primary outcome was the incidence of parent-reported fever needing rescue acetaminophen, and the secondary outcome was the incidence of local side-effects.

Results: There was a statistically significant higher incidence of fever and irritability in the 1st 6 hours following vaccination in the as-needed group (p = 0·04). No difference was observed in the incidence of local and systemic side-effects or the median number of acetaminophen doses required by the children in the two groups.

Conclusions: Routine prophylactic acetaminophen after DPT vaccination was effective in reducing the frequency of fever and irritability in the initial 6 hours. However, given that a similar number of doses of acetaminophen was required in both groups, it seems inappropriate to expose all infants receiving DPT vaccination to the possible adverse effects of routine administration of acetaminophen.