We conducted a cross-sectional study to explore whether clinical characteristics and autism diagnostic-traits severity are associated with caregiver-reported impairment of health-related quality of life (Pediatric Quality of Life Inventory Generic Core Scales, Fourth Edition) in 93 Chilean toddlers (age: 2-4 years) with autism spectrum disorder. Median total scale, physical health, and psychosocial health scores were 76 (IQR 70-81), 88 (IQR 81-94), and 71 (IQR 62-79), respectively. In multiple-regression analysis, diagnostic age (beta = 0.219; p 0.021) and Calibrated Severity Score of Autism Diagnostic Observation Schedule, second edition (beta = - 0.434; p < 0.001) were independently correlated to the total scale score. Lower age and higher autistic traits severity at diagnosis are correlated with worse well-being perception by caregivers.