Display omitted •The reactogenicity and safety of a liquid PCV-free HRV were assessed.•Adverse event rates were similar for the liquid PCV-free HRV and the lyophilized HRV.•In both groups, about 6% of infants reported at least one serious adverse event.•The liquid PCV-free HRV has a favorable safety profile. The introduction of rotavirus vaccines in national immunization programs has decreased mortality and hospitalizations due to diarrhea. GSK’s live-attenuated, human rotavirus vaccine (HRV) is a 2-dose vaccine for oral administration. Following the detection of porcine circovirus type 1 (PCV-1) in HRV, a PCV-free (no detection of PCV-1 and PCV-2 according to the detection limits of tests used) HRV was developed. The immunogenicity, reactogenicity and safety of a liquid (liq) PCV-free HRV were assessed in two prior studies. The present study aimed to generate additional reactogenicity and safety data. This phase III, observer-blind, randomized, controlled multi-country study enrolled healthy 6–12-week-old infants. Infants were randomized to receive 2 doses of either the liq PCV-free HRV (N = 677) or the lyophilized (lyo) HRV (N = 674) 1–2 months apart. Solicited adverse events (AEs) were recorded for 8 days after each dose, unsolicited AEs for 31 days and serious AEs (SAEs) from dose 1 until the end of the 6-month safety follow-up. The occurrence of solicited general AEs was comparable between the liq PCV-free HRV and the lyo HRV groups, with irritability/fussiness being the most frequently reported (74.9% 95% confidence interval: 71.4–78.1 and 72.1% 68.6–75.5). Unsolicited AEs were reported for 29.7% (26.3–33.3) and 30.6% (27.1–34.2) of infants in the liq PCV-free HRV and the lyo HRV group. A total of 39 and 38 infants reported at least one SAE, respectively. The most common SAEs were upper respiratory tract (0.7% and 0.9%) and urinary tract infections (0.9% and 0.6%). One SAE (constipation) in the liq PCV-free HRV group was considered as potentially causally related to vaccination by the investigator. No deaths were reported. The study showed that the reactogenicity and safety profiles of the liq PCV-free HRV and the lyo HRV are similar. ClinicalTrials.gov identifier: NCT03954743.