The aim of this study was to evaluate the effect of haemophilia disease severity and potential intermediaries on body mass index (BMI) in patients with haemophilia. A secondary analysis of a cross-sectional study of 88 adults with haemophilia was undertaken. On bivariate analysis, persons with severe haemophilia had 9.8% lower BMI (95% CI −17.1, −3.0) than persons with non-severe haemophilia. The effect of haemophilia severity on BMI varied significantly by human immunodeficiency virus (HIV) status. Among HIV-positive subjects, haemophilia severity was not associated with BMI (+5.0%, 95% CI −22.4, 41.9). Among HIV-negative subjects, severe haemophilia was associated with 15.1% lower BMI (95% CI, −23.6, −5.7). Older (>41 years) HIV-negative subjects with severe haemophilia had a BMI that was 24.8% lower (95% CI −39.1, −7.0) than those with non-severe haemophilia. No statistically significant association was detected between BMI and severe vs. non-severe haemophilia for younger HIV-negative subjects. Although joint disease, as measured by the World Federation of Hemophilia (WFH) joint score, did not influence the association between haemophilia disease severity and BMI, adjustment for the atrophy component of the WFH score reduced the association between haemophilia severity and BMI by 39.1–69.9%. This suggested that muscle atrophy mediated at least part of the relationship between haemophilia severity and BMI. Haemophilia disease severity is associated with BMI and appears to be mediated by muscle atrophy of surrounding joints. This association appears to be modified by HIV status and possibly age.