Purpose: The present study addresses the natural history ocular alignment in infantile esotropia that presents at 2 to 4 months of age. Methods: Eye alignment during the first 6 months of life was evaluated in two cohorts of healthy infants who initially had esotropia at 2 to 4 months of age; 80 infants were enrolled in a prospective study at the Retina Foundation of the Southwest (RFSW), and 41 infants were reviewed retrospectively as a pilot study for the Early Surgery for Congenital Esotropia (ESCET) multicenter trial. In addition, 79 of the 80 children in the RFSW cohort were reexamined at 4.5 years of age or older for ocular alignment and stereopsis. Results: Among infants who initially had constant esotropia ≥40 PD, 0 of 45 children in the RFSW cohort and 0 of 21 children in the ESCET cohort showed resolution to orthophoria. In addition, only 2 infants showed a reduction in angle of deviation below 40 PD (one to 35 PD and one to 20 PD). Resolution to orthophoria was noted in a few infants who initially had small angle or variable angle esotropia. On follow-up at 4.5 years of age or greater, 91% of the children in the RFSW cohort had alignment within 8 PD of orthoposition and 30% had stereoacuity of 3000″ to 60″. Children who underwent surgical alignment at 6 months of age had a higher prevalence of coarse stereopsis than children who underwent alignment at 7 to 15 months of age. Conclusions: Taken together, these results suggest that infants who present at 2 to 4 months of age with constant esotropia of 40 PD or greater are valid candidates for surgical treatment. In addition, data from long-term follow-up support the hypothesis that early surgical alignment may promote the development of at least coarse stereopsis in these infants.