BACKGROUND: One in five children visiting a homeopathic physician suffers from atopic eczema. OBJECTIVES: We aimed to examine the long-term effectiveness, safety and costs of homoeopathic vs. conventional treatment in usual medical care of children with atopic eczema. METHODS: In this prospective multi-centre comparative observational non-randomized rater-blinded study, 135 children (48 homoeopathy, 87 conventional) with mild to moderate atopic eczema were included by their respective physicians. Depending on the specialisation of the physician, the primary treatment was either standard conventional treatment or individualized homeopathy as delivered in routine medical care. The main outcome was the SCORAD (SCORing Atopic Dermatitis) at 36 months by a blinded rater. Further outcomes included quality of life, conventional medicine consumption, safety and disease related costs at six, 12 and 36 months after baseline. A multilevel ANCOVA was used, with physician as random effect and the following fixed effects: age, gender, baseline value, severity score, social class and parents' expectation. RESULTS: The adjusted mean SCORAD showed no significant differences between the groups at 36 months (13.7 95% CI [7.9-19.5] vs. 14.9 [10.4-19.4], p = 0.741). The SCORAD response rates at 36 months were similar in both groups (33% response: homoeopathic 63.9% vs. conventional 64.5%, p = 0.94; 50% response: 52.0% vs. 52.3%, p = 0.974). Total costs were higher in the homoeopathic versus the conventional group (months 31-36 200.54 Euro [132.33-268.76] vs. 68.86 Euro [9.13-128.58], p = 0.005). CONCLUSIONS: Taking patient preferences into account, while being unable to rule out residual confounding, in this long-term observational study, the effects of homoeopathic treatment were not superior to conventional treatment for children with mild to moderate atopic eczema, but involved higher costs.