Background: Conflicting results exist concerning disease knowledge and patients' quality of life (QOL) while there is very limited information concerning the impact of awareness on caregivers' health‐related quality of life. The aim of this study was to explore the influence of disease awareness on both cancer patients and their caregivers during the period of chemotherapy. Materials and Methods: Two hundred and twelve cancer patient–caregiver dyads completed the QOL SF‐36 instrument on the day of chemotherapy. Hierarchical multiple linear regression analysis was performed. Results: Physical component parameters were significantly higher in the family members (p<0.001), while their mental component was lower than cancer patients. Younger patients, females, and of higher educational status were more frequently aware of their disease status while patients with gastrointestinal cancer were more likely to be unaware. Disease knowledge seems to exert a negative influence on patients' physical and mental parameters while lack of awareness affects adversely caregivers' vitality, social function, emotional role, and mental health. Multiple regression analysis confirmed disease awareness affected reversely patients' and caregivers' mental QOL while the counter‐influence of the dyad was revealed. Conclusions: A holistic approach to cancer management should be followed. Patient's treatment is the major medical concern, but health system and professionals should be involved in the mental and physical support of caregivers as well. Tailored interventions that focus on the support of the dyad patient–caregiver should be developed. Copyright © 2010 John Wiley & Sons, Ltd.