Background Chronic diseases and multimorbidity are a major cause of disease burden-for patients, caregivers, and society. Little is known however about potential interaction effects between specific disease combinations. Besides an additive effect, the presence of multiple conditions could also act synergistically or antagonistically regarding the impact on patients' health-related quality of life (HRQoL). The aim was to estimate the impact of coexisting chronic diseases on HRQoL of the adult general Belgian population. Methods The Belgian Health Interview Survey 2018 provided data on self-reported chronic conditions and HRQoL (EQ-5D-5L) for a nationally representative sample. Linear mixed models were used to analyze two-way and three-way interactions of disease combinations on HRQoL. Results Multimorbidity had a prevalence of 46.7% (>= 2 conditions) and 29.7% (>= 3 conditions). HRQoL decreased considerably with the presence of multiple chronic diseases. 14 out of 41 dyad combinations and 5 out of 13 triad combinations showed significant interactions, with a dominant presence of negative/synergistic effects. Positive/antagonistic effects were found in more subjective chronic diseases such as depression and chronic fatigue. Conditions appearing the most frequently in significant disease pair interactions were dorsopathies, respiratory diseases, and arthropathies. Conclusions Diverse multimorbidity patterns, both dyads and triads, were synergistically or antagonistically associated with lower HRQoL. Tackling the burden of multimorbidity is needed, especially because most disease combinations affect each other synergistically, resulting in a greater reduction in HRQoL. Further knowledge about those multimorbidity patterns with a greater impact on HRQoL is needed to better understand disease burden beyond mortality and morbidity data.