Young people on the autistic spectrum (AS) may be at an increased risk of developing mental health difficulties, but to date research evidence has been equivocal and/or inadequate. The aim of the current study was to document the mental health profiles of adolescents on the AS, and to identify factors that contribute to difficulties in this area. Mental health profiles of a group of adolescents on the AS (N = 22) were compared with age, gender and special educational needs (SEN)-provision-matched control groups of adolescents with dyslexia (N = 21) and with no SEN (N = 23) using the Beck Youth Inventories. Additionally, five participants on the AS participated in semi-structured interviews about their experience of school. Quantitative analysis demonstrated that adolescents on the AS experienced significantly greater anxiety, depression, anger and lower self-concept than those with no SEN. They also experienced significantly greater anxiety and anger than those with dyslexia. Qualitative analysis revealed that problems in social relationships, understanding the nature of the AS and disruptions to routine were common contributory factors to the mental health difficulties of participants. However, interview data also revealed key coping strategies implemented by participants to help them overcome their difficulties. The implications of these findings are discussed, and methodological limitations are noted.