Follow-up care in adult childhood cancer survivors (ACCS) aims to screen for, prevent, and treat potential late effects. The trajectory of ACCS' health-related quality of life (HRQoL) attending follow-up care is unclear. We investigated changes in HRQoL of ACCS attending a follow-up care program. The primary outcome was the minimal clinically important decrease (MCID) in HRQoL of ≥ 5 points in the mental (MCS) and/or physical component score (PCS) of the 36-item Short Form (SF-36) between baseline and follow-up (3-months after the first visit). We compared baseline characteristics, psychological factors, satisfaction, and distress (measured using the Brief Symptom Inventory). In 47 ACCS (100%), no significant change in the overall median MCS and PCS was observed. In 14 ACCS (29.8%) a MCID in HRQoL was observed. Compared to ACCS without a MCID, they reported lower PCS (median 45.2 [31.7
51.4] vs. 55.6 [46.1
57.6], p = 0.007), a higher proportion of low physical health (PCS <
48
71.4% vs. 27.3%, p = 0.009) and distress (50% vs. 18.8%, p = 0.030) at baseline. Satisfaction was high (94.9%). One in three ACCS experienced a clinically important decrease in HRQoL after follow-up care, with higher rates in those with lower physical health and higher psychological distress at baseline.