The present study aims to investigate the course of psychological symptoms through chemotherapy in a sample of primary caregivers of patients with cancer and to examine all possible correlations between psychological distress and demographic characteristics. In this prospective study, 112 primary family caregivers of cancer patients were evaluated. Symptom checklist 90 revised (SCL-90-R) was administered to assess their pathological symptoms, the Hospital Anxiety and Depression Scale (HADS) to assess depression and anxiety. There was an evaluation at the beginning of chemotherapy and a second at the end of the patients’ intravenous chemotherapy treatment (EOT). A total of 112 primary caregivers were initially enrolled in the study, and 99 (88.4%) completed it. Caregivers’ psychopathology was low to moderate at both points of time (baseline and EOT). However, a considerable decrease in the Global Severity Index (GSI) emerged over time. At EOT, participants reported statistically significant decreases in five aspects of SCL 90, namely Depression, phobic anxiety, obsessive–compulsive symptoms, somatization, and psychoticism. A notable finding was that female caregivers were significantly more distressed, especially when providing care to a male recipient.