OBJECTIVES:   To investigate the cross-over effects on health-related quality of life (HRQoL) in an randomized cross-over design study for hemophilia-A patients. METHODS: HRQoL via SF-36 Health Survey was measured every 3 months in a prospective, randomized, cross-over, investigator-initiated study comparing 6 months of AICC infused prophylaxis (PX) with 6 months of on-demand (OD) therapy, separated by a 3-month washout period during which patients used on-demand therapy. HRQoL was summarized in two continuous variables: Physical Component Score (PCS-36) and Mental Component Score (MCS-36). The difference between two study periods for 6-month change from baseline in PCS-/MCS-36 are compared using Wilcoxon signed-rank test to measure the difference between two groups regardless of the sequence of medications. To investigate the effect of random sequence in the change of HRQoL, the difference between two study periods for 6-month change from baseline in PCS-/MCS-36 is compared by random sequence using Wilcoxon-Mann-Whitney U test with exact statement.  RESULTS:  Twenty-six patients completed both study periods.  17 of them were >14 years old and thus completed QoL questionnaires and are included in this analysis. The difference between PX and OD in 6-month change from baseline was 2.83 for PCS-36 (p=0.378) and 1.29 for MCS-36 (p=0.890), favored PX on both measures. Regardless of random sequence of medication, HRQoL showed a moderate improvement with PX. When comparing the difference of 6-month change by treatment sequence, patients who initiated with PX then switched to OD had a greater improvement compared to the opposite sequence (PX->OD: 6.59, OD->PX: 0.19 for PCS-36 (p=0.475); PX→OD: 2.66, OD→PX: 0.33 for MCS-36 (p=0.601)). CONCLUSIONS: A cross-over effect, albeit statistically non-significant, was observed when the difference of 6-month change was compared by treatment sequence. Patients who started with more favorable medication tended to show a greater improvement, whereas patients in opposite sequence showed a slight improvement.