Background <p>To assess a framework for pediatric medication acceptance evaluation while measuring variability in the taste of liquid clindamycin and the occurrence of side effects.</p> Methods <p>Children receiving their first clindamycin prescription and a caregiver participated in a prospective cohort study. After practicing using the hedonic-face scale to rate water, we videotaped children rating clindamycin palatability immediately, 5-, and 10-min post-swallow. Recordings were coded for behavioral responses. Caregivers rated children’s acceptance on test day and at treatment end and completed daily diaries and an exit interview on adherence, side effects, and clinical outcomes. Genome-wide genotyping probed whether genetic ancestry and selected candidate genetic variants were associated with taste ratings and side effects.</p> Results <p>While only 2% (1/67) disliked water, 54% (36/67) disliked the taste of clindamycin immediately post-swallow and were more likely to display facial expressions of distaste (<i>p</i> &lt; 0.001). Child and caregiver ratings moderately agreed (<i>κ</i> = 0.51). Side effects occurred in 36% (24/67) of children. Hedonic ratings and side effects did not differ significantly by genetic ancestry or associate with <i>TAS2R38</i> rs713598 or <i>TRPA1</i> rs11988795 genotypes.</p> Conclusion <p>This study highlights substantial variability in pediatric medicine palatability and side effects and introduces a validated framework for assessing individual differences.</p> Impact <p><UnorderedList Mark="Bullet"> <ItemContent> <p>We developed a validated framework to document individual differences in medication palatability, side effects, and caregiver perceptions and practices in both remote and onsite settings.</p> </ItemContent> <ItemContent> <p>There was substantial variability in hedonic ratings of palatability and side effects of clindamycin used for standard of care treatment in children.</p> </ItemContent> <ItemContent> <p>Hedonic ratings and side effects did not differ significantly by genetic ancestry or associate with TAS2R38 rs713598 or TRPA1 rs11988795 genotypes.</p> </ItemContent> <ItemContent> <p>We introduce a new framework for assessing individual differences in palatability for liquid pediatric medicines.</p> </ItemContent> </UnorderedList></p>