Purpose Psychosocial health (PH) and quality of life (QoL) are important health outcomes. We compared PH and QoL of adolescents conceived with intrazytoplasmatic sperm injection (ICSI) and of naturally conceived controls. The impact of disclosure of ICSI-conception on QoL and PH was quantified. Methods The cross-sectional sample consisted of 545 ICSI-conceived adolescents and 427 unmatched singleton controls aged 14–18 years. Adolescents reported PH with the ‘Strengths and Difficulties Questionnaire’ (low values indicating high PH), and QoL with the KINDL questionnaire (high values indicating high QoL). Because of clustering of multiples within families, adjusted linear regressions with generalized estimating equations were used to compare ICSI- and naturally conceived adolescents. Missing values were treated by multiple imputation. Minimal importance was defined as half a standard deviation. Results Both ICSI and control adolescents had high PH (low mean ‘total difficulties’ score: 9 of 40) and high QoL (mean ‘total KINDL’ score: 75 of 100). Differences were generally in favour of the ICSI group. Significant differences occurred for ‘impact of behavioural problems’ ( p  = 0.033), the ‘total KINDL’ score ( p  = 0.021) and the dimensions ‘physical wellbeing’ ( p  = 0.031) and ‘school’ ( p  = 0.005), but all differences were far below minimal importance. About 80% of ICSI adolescents were informed about their mode of conception. PH and QoL were slightly higher in informed adolescents; behavioural difficulties (‘total behavioural problems’ and ‘conduct problems’) were significantly lower ( p  = 0.013 and p  = 0.003), behavioural strengths (‘prosocial behaviour’) and ‘physical QoL’ significantly higher ( p  = 0.004 and p  = 0.018), but differences remained clearly below minimal importance. Conclusions Our results are reassuring for parents using ICSI and their children. Speaking openly about an ICSI conception in the family may be beneficial.