Background: Cancer patients increasingly seek second opinion (SO) consultations, but there is scarce empirical evidence to substantiate medical and psychological benefits for patients. This is the first study to examine patient- and oncologist-reported (1) motivations and expectations of patients to seek a SO, (2) the perceived medical outcome, and (3) psychological consequences of SOs over time (i.e. patients’ uncertainty and anxiety). Material and methods: This multi-informant longitudinal cohort study (SO-COM) included consecutive cancer patients referred for a SO (N = 70; age 28–85), as well as their referring and consulting oncologists. Outcome measures were completed at three time points: Patients and referring oncologists reported motivations and expectations before the SO (T0), patients and consulting oncologists reported the medical outcome of the SO (i.e. discrepancy between first and second opinion) immediately following the SO (T1), and patients reported their uncertainty and anxiety at T0, T1, and two months following the SO (T2). Results: Cancer patients most frequently reported wanting expert advice, exhausting all options, and/or needing more information as motivations for SOs. Referring oncologists rather accurately anticipated these motivations, except most did not recognize patients’ information needs. The vast majority of patients (90.0%) received a medical advice similar to the first opinion, although 65.7% had expected to receive a different opinion. Patients’ uncertainty (F = 6.82, p=.002; η2 =.22), but not anxiety (F = 3.074, p=.055, η2 =.11) was significantly reduced after the SO. Conclusions: SOs can yield psychological benefits by reducing patients’ uncertainty, but the added medical value remains debatable. Referring oncologists may not be fully aware of their patients’ information needs. Patients should be better informed about goals and benefits of SOs to better manage their expectations. More cost-effective ways of optimally providing medically and psychologically valuable SOs need to be explored.