BackgroundWith declining malaria prevalence and improved use of malaria diagnostic tests, an increasing proportion of children seen by community health workers (CHWs) have unclassified fever. Current community management guidelines by WHO advise that children seen with non-severe unclassified fever (on day 1) should return to CHWs on day 3 for reassessment. We compared the safety of conditional follow-up reassessment only in cases where symptoms do not resolve with universal follow-up on day 3.Methods and findingsWe undertook a 2-arm cluster-randomised controlled non-inferiority trial among children aged 2–59 months presenting with fever and without malaria, pneumonia, diarrhoea, or danger signs to 284 CHWs affiliated with 25 health centres (clusters) in Southern Nations, Nationalities, and Peoples’ Region, Ethiopia. The primary outcome was treatment failure (persistent fever, development of danger signs, hospital admission, death, malaria, pneumonia, or diarrhoea) at 1 week (day 8) of follow-up. Non-inferiority was defined as a 4% or smaller difference in the proportion of treatment failures with conditional follow-up compared to universal follow-up. Secondary outcomes included the percentage of children brought for reassessment, antimicrobial prescription, and severe adverse events (hospitalisations and deaths) after 4 weeks (day 29). From December 1, 2015, to November 30, 2016, we enrolled 4,595 children, of whom 3,946 (1,953 universal follow-up arm; 1,993 conditional follow-up arm) adhered to the CHW’s follow-up advice and also completed a day 8 study visit within ±1 days. Overall, 2.7% had treatment failure on day 8: 0.8% (16/1,993) in the conditional follow-up arm and 4.6% (90/1,953) in the universal follow-up arm (risk difference of treatment failure −3.81%, 95% CI −∞, 0.65%), meeting the prespecified criterion for non-inferiority. There were no deaths recorded by day 29. In the universal follow-up arm, 94.6% of caregivers reported returning for reassessment on day 3, in contrast to 7.5% in the conditional follow-up arm (risk ratio 22.0, 95% CI 17.9, 27.2, p < 0.001). Few children sought care from another provider after their initial visit to the CHW: 3.0% (59/1,993) in the conditional follow-up arm and 1.1% (22/1,953) in the universal follow-up arm, on average 3.2 and 3.4 days later, respectively, with no significant difference between arms (risk difference 1.79%, 95% CI −1.23%, 4.82%, p = 0.244). The mean travel time to another provider was 2.2 hours (95% CI 0.01, 5.3) in the conditional follow-up arm and 2.6 hours (95% CI 0.02, 4.5) in the universal follow-up arm (p = 0.82); the mean cost for seeking care after visiting the CHW was 26.5 birr (95% CI 7.8, 45.2) and 22.8 birr (95% CI 15.6, 30.0), respectively (p = 0.69). Though this study was an important step to evaluate the safety of conditional follow-up, the high adherence seen may have resulted from knowledge of the 1-week follow-up visit and may therefore not transfer to routine practice; hence, in an implementation setting it is crucial that CHWs a...