OBJECTIVE: Early childhood development programs typically combine healthy nutrition and cognitive stimulation in an integrated model. We separately delivered these 2 components in a cluster-randomized controlled trial to evaluate their comparative effectiveness in promoting healthy child development and caregiver mental health. This is the first study to do so for HIV-affected children and their infected mothers. METHODS: Two hundred twenty-one HIV-exposed but uninfected child (2-3 years old) and caregiver dyads in 18 geographic clusters in Eastern Uganda were randomized by cluster to receive biweekly individualized sessions of either (1) Mediational Intervention for Sensitizing Caregivers (MISC) training emphasizing cognitive stimulation or (2) Uganda Community Based Association for Child Welfare (UCOBAC) program that delivered health and nutrition training. Children were evaluated at baseline, 6 months, 1 year (training conclusion), and 1-year posttraining with the Mullen Scales of Early Learning (MSEL), the Color-Object Association Test for memory, the Early Childhood Vigilance Test of attention, and the Behavior Rating Inventory of Executive Function (BRIEF-parent). The Caldwell Home Observation for the Measurement of the Environment (HOME) was completed by observers to gauge caregiving quality after training. Caregiver depression/anxiety (Hopkins Symptom Checklist-25) and functionality (list of activities of daily living) were also evaluated. Data collectors were blinded to trial arm assignment. RESULTS: Mediational Intervention for Sensitizing Caregivers resulted in significantly better quality of caregiving compared with UCOBAC midintervention with an adjusted mean difference (MadjDiff) of 2.34 (95% confidence interval [CI]: 1.54-3.15, p < .01), postintervention (MadjDiff = 2.43, 95% CI: 1.61-3.25, p < .01), and at 1-year follow-up (MadjDiff = 2.07, 95% CI: 1.23-2.90, p < .01). MISC caregivers reported more problems on the BRIEF for their child at 1-year posttraining only (p < .01). Caregiving quality (HOME) was significantly correlated with MSEL composite performance 1-year posttraining for both the MISC and the UCOBAC trial arms. Likewise, physical growth was significantly related to child development outcomes even though it did not differ between trial arms. CONCLUSION: Even though MISC demonstrated an advantage of improving caregiving quality, it did not produce better child cognitive outcomes compared with health and nutrition training. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01640561.