This paper examined the differential influences of personal, interpersonal, and environmental level factors on domain-based and overall life satisfaction over one year for youth with chronic health conditions. Baseline and Time 2 follow-up data were used from a study examining quality of life for a sample of 439 youth with chronic conditions, aged 11 to 17 years. The Brief Multidimensional Students’ Life Satisfaction Scale measured youths’ life satisfaction in five domains (i.e., satisfaction with self, family life, friendships, school experiences, where one lives) and in overall life. Six multivariate linear regression analyses were performed, each exploring relations of the hypothesized correlates at baseline with one aspect of life satisfaction at follow-up controlling for youth gender, age, household income, and the corresponding aspect of life satisfaction at baseline. Factors at all three levels were found to be important to some aspect of life satisfaction. Emotional well-being played a notable role in life satisfaction across multiple domains and in overall life satisfaction. Family-related factors were also significantly related to life satisfaction across several domains. Social support from close friends and teachers and the school environment were important to specific domains of life satisfaction. Classmate social support emerged as a key factor related to overall life satisfaction. Implications for practice and future research are discussed.