The clinical benefits of prophylactic FVIII/IX therapy versus treatment on-demand (episodic) in people with severe hemophilia (PwSH) in the US are well understood; however, there has been little investigation into comparative treatment burden of prophylaxis vs on-demand therapy. The objective of the analysis was to examine the relationship between treatment regimen and key clinical and employment outcomes in PwSH in the US. This analysis draws data from the ‘Cost of Severe Hemophilia Across the US: A Socioeconomic Survey’ (CHESS US+), a cross-sectional study in PwSH. Adult PwSH completed a questionnaire that collected 12 months of retrospective data across measures of clinical, economic, and humanistic burden. We examined annual bleeding rate (ABR) along with other clinical variables and measures of labor force participation. Results are presented as mean (standard deviation) or N (%). Of 354 PwSH, 261 (74%) received a prophylaxis regimen and 93 (26%) on-demand therapy. Mean age was lower in the prophylaxis group [33.99 (11.21) vs. 37.71 (14.21)], while target joints and problem joints were similarly prevalent. Mean ABR in prophylaxis patients was lower compared with on-demand: 5.44(6.97) vs. 7.49 (11.68). Full-time and part-time employment rates were similar across treatment groups, while the unemployment rate was higher among people on prophylaxis (23.4% vs. 15%). PwSH employed part-time cited hemophilia as the reason, in 35% (prophylaxis) vs. 25% (on-demand) of cases. Among PwSH who retired early or who stopped working, haemophilia was cited as the reason in 70% (prophylaxis) vs. 17% (on-demand) of cases. Despite better clinical outcomes compared to on-demand patients, the findings of this analysis suggest that PwSH on a prophylaxis regimen may encounter barriers to maintaining full-time employment. Further research is warranted to gain a better understanding of these barriers, which may help reduce this negative socio-economic impact on people with severe hemophilia in the US.