OBJECTIVE: To investigate whether a responsive stimulation intervention delivered to caregivers of young children either alone or integrated with nutrition interventions would benefit parenting skills and emotional availability to promote children's development and growth compared with either a nutrition intervention alone or the usual standard of care. METHODS: A cluster randomized factorial effectiveness trial was implemented in an impoverished community in Pakistan. The 4 trial arms were control (usual standard of care), responsive stimulation (responsive care and stimulation), enhanced nutrition (education and multiple micronutrients), and a combination of both enriched interventions. The 4 intervention packages were delivered by community health workers to 1489 mother-infant dyads in the first 2 years of life. Parenting skills and emotional availability indexed by mother-child interaction, caregiving environment, knowledge and practices pertaining to early childhood care and feeding, and maternal depressive symptoms were assessed at multiple intervals. An intention-to-treat factorial analysis was conducted. RESULTS: Intervention groups were comparable at baseline. Responsive stimulation significantly benefitted parenting skills with large effect sizes on mother-child interaction (Cohen's d 0.8), caregiving environment (Cohen's d 0.9-1.0), and knowledge and practices (Cohen's d 0.7-1.1) compared with small-modest significant effects as a result of nutrition intervention on mother-child interaction and caregiving environment only (Cohen's d 0.4 and 0.2, respectively). The combined intervention had a small significant effect on decreasing maternal depressive symptoms over time (Cohen's d 0-0.2). CONCLUSIONS: A responsive stimulation intervention can promote positive caregiving behaviors among impoverished families. Additional research is needed on interventions to reduce maternal depressive symptoms.