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HIV infection places children at neurodevelopmental risk; for young children in poverty, risk is compounded by compromised caregiving quality. The mediational intervention for sensitizing caregivers (MISC) program trained caregivers on fostering daily interactions with young children. We hypothesized that MISC could enhance neurodevelopment of rural Ugandan HIV-infected children and improve mental health outcomes of their caregivers, which might mediate improved caregiving quality.A randomized trial of HIV-infected young children (ages 2–5 years) and their female caregivers; cluster randomization was to MISC or a nutrition curriculum.A total of 18 geographic clusters in rural Uganda.Children and caregivers were evaluated at baseline, 6 months, 1 year, and 1-year post-training.Mullen Scales of Early Learning, the Color-Object Association Test for memory, the Early Childhood Vigilance Test of attention, and the Behavior Rating Inventory of Executive Function for the children. Caregivers completed measures of depression and anxiety symptoms and daily functioning.MISC had a significant impact on postintervention receptive language (adjusted mean difference = 3.13, 95% confidence interval 0.08, 6.18) that persisted at 1-year follow-up. MISC caregivers reported significantly less functional impairment postprogram (adjusted mean difference = −0.15, 95% confidence interval −0.28, −0.01). Other outcomes were NS.Both intervention conditions resulted in improvements in the study children over time. MISC showed additional impacts on child language and caregiver well-being. Future directions that include assessing the extent enhanced language development resulting from improved caregiving may better prepare impoverished children for school.