Research on adaptive human behaviour often emphasizes goal attainment, alongside optimism, self-efficacy, and persistence. Recently, it has been suggested that giving up personal goals when the latter are unattainable is equally important. The present study extends previous findings to a clinical population of multiple sclerosis (MS) patients and examines whether goal disengagement and re-engagement are related to psychological well-being, illness representation, and disease characteristics (duration and stage). One hundred and one MS patients filled out questionnaires pertaining to goal disengagement (GD) and goal re-engagement (GR), anxiety, depression, purpose in life, illness intrusion, illness perception, and background variables. GD and GR had good reliability also in this population and were uncorrelated. Regression analyses yielded significant results only on depression. An interaction between goal disengagement and re-engagement on depression was uncovered, so that those who were high on disengagement and low on re-engagement were more affected by depression. Unexpectedly, the least depressed are those low on both disengagement and re-engagement. The difference between populations of healthy individuals as compared to patients is discussed. Limitation of the cross-sectional design is highlighted with respect to directionality between depression and change in goals.