It is often assumed that brain tumor patients' significant others (SOs: partners, other family members or close friends) may face greater stress than those of patients with malignancies not involving the central nervous system (CNS), due to progressive changes in neurological and cognitive functioning. We compared health-related quality of life (HRQOL) of SOs of patients with high-grade glioma (HGG) and low-grade glioma (LGG) with that of SOs of patients with non-CNS tumors with similar prognosis and at a similar phase in the disease trajectory (i.e. non-small cell lung cancer (NSCLC) and low-grade hematological malignancies (NHL/CLL), respectively). HRQOL of SOs and patients was assessed using the Short Form-36 (SF-36) Health Survey. Patients' neurological functioning was indexed and they underwent comprehensive neurocognitive testing. SOs of 213 LGG patients, 99 NHL/CLL patients, 55 HGG patients and 29 NSCLC patients participated. The SOs of LGG and NHL/CLL patients reported similar levels of HRQOL. SOs of HGG patients reported significantly lower mental health scores (MCS; p = 0.041) and social functioning (p = 0.028) than those of NSCLC patients. Mental health scores (MCS) of HGG and NSCLC patients were associated significantly with the mental health of their SOs (p = 0.013 and p < 0.001, respectively). Surprisingly, HGG patients' cognitive and neurological functioning were not predictive of SOs' mental health at the multivariate level. SOs of patients with highly malignant CNS tumors in the acute phase are at increased risk of compromised HRQOL compared to those of patients with systemic tumors without CNS involvement and a comparable life expectancy.