OBJECTIVE: To evaluate the effect of a lifestyle intervention on fatigue, participation, quality of life, gross motor functioning, motivation, self-efficacy and social support, and to explore mediating effects of physical behavior and physical fitness. DESIGN: A randomized controlled trial with intention to treat analysis. SETTING: Rehabilitation centers in university hospitals in the Netherlands. SUBJECTS: Adolescents and young adults with spastic cerebral palsy. INTERVENTIONS: A six-month lifestyle intervention that consisted of physical fitness training combined with counseling sessions focused on physical behavior and sports participation. MAIN MEASURES: Fatigue, social participation, quality of life and gross motor functioning. RESULTS: The lifestyle intervention was effective in decreasing fatigue severity during the intervention (difference -6.72, p = 0.02) and in increasing health-related quality of life with respect to bodily pain (difference 15.14, p = 0.01) and mental health (difference 8.80, p = 0.03) during follow-up. Furthermore, the domain participation and involvement of the social support increased during both the intervention (difference 5.38, p = 0.04) and follow-up (difference 4.52, p = 0.03) period. Physical behavior or physical fitness explained the observed effects for 22.6%, 9.7% and 28.1% of improvements on fatigue, bodily pain and mental health, but had little effect on social support (2.6%). INTERPRETATION: Fatigue, bodily pain, mental health and social support can be improved using a lifestyle intervention among adolescents and young adults with cerebral palsy. Furthermore, substantial mediating effects were found for physical behavior and physical fitness on fatigue, bodily pain and mental health. TRIAL REGISTRATION: Nederlands Trial Register NTR1785.

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