Objective: To explore the associations of general health-related quality of life (GHRQOL) with strabismus or amblyopia in preschool children. Design: Population-based study. Participants: Sample of children aged 25 to 72 months in the Multi-ethnic Pediatric Eye Disease Study (MEPEDS). Methods: The Pediatric Quality of Life Inventory (PedsQL), a measure of GHRQOL, was administered to the parents of the children. Main Outcome Measures: The PedsQL consists of 4 subscales (physical, emotional, social, and school functioning) and 3 composite scores (physical summary, psychosocial summary, and total). Regression models were used to evaluate the associations of GHRQOL with strabismus (in children 25-72 months) or amblyopia (in children 30-72 months). Results: Of the 4218 children aged >= 25 months, 121 (2.9%) were diagnosed with strabismus. Significant differences were found in all 3 composite scores between children with and without strabismus, before and after controlling for gender, age, race, family income, systemic health conditions, and prior knowledge of strabismus diagnosis (P < 0.05). These differences were present in esotropes, exotropes, children with intermittent strabismus, and children with constant strabismus. A total of 3318 children were aged >= 30 months, and 71 children (2.1%) had amblyopia. There were no significant differences in any PedsQL scores between children with and without amblyopia, even after adjusting for gender, age, race, and family income (P > 0.05). Conclusions: Strabismus was associated with significantly worse GHRQOL in preschool children. Although we did not find any detectable association between amblyopia and GHRQOL, further study using vision-specific instruments is required to explore the impact of both strabismus and amblyopia on pediatric quality of life.