Quality of life is often severely impaired in people with schizophrenia, and adherence to antipsychotic medication has been consistently found to be low in this population. Although there is a considerable amount of evidence on these two variables in schizophrenia research, there is only limited knowledge on how they relate to one another. The aim of this study is to develop a meaningful model of the relationship between quality of life and adherence that includes mediating variables. A multicenter randomized controlled trial recruited 409 subjects in London, Verona, Amsterdam, and Leipzig. Baseline interviews obtained data on adherence, quality of life, and other variables. We used graphical modeling to investigate the relationships between the variables. No direct relation could be discerned between subjective quality of life and adherence to medication. Mediating variables, most importantly symptomatic impairment, global functioning, and medication side effects, were identified by the model. It can be concluded that, when aiming at the improvement of quality of life in people with schizophrenia, variables other than adherence, i.e., symptomatic impairment, global functioning, and medication side effects, should be targeted.