Purpose: Despite significant antiemetic advances, almost 50 % of treated cancer patients still experience nausea and vomiting (N&V). The goal of antiemetic therapy - complete prevention of treatment-induced nausea and/or vomiting (TIN+/-V) - remains elusive for several reasons. Potentially, N&V may be part of a symptom cluster where co-occurring symptoms negatively affect antiemetic management. Consequently, we examined TIN+/-V incidence and the impact of nausea, vomiting and symptom cluster(s) containing them, respectively, on patients' quality of life (QoL) and psychological adjustment across treatment. Methods: A longitudinal secondary analysis was performed on data from a prospective, observational QoL study involving 200 newly diagnosed cancer patients who underwent combined modality treatment. QoL, psychological adjustment and patient/clinical characteristics were examined at pretreatment, on-treatment (8 weeks) and post-treatment. Results: Overall, 62 % of patients experienced TIN+/-V, with TIN (60 %) doubling TIV incidence (27 %). Exploratory factor analyses of QoL scores at each treatment time point identified a recurrent gastrointestinal symptom cluster comprising nausea, vomiting and appetite loss. Approximately two thirds of patients reported co-occurrence of all three symptoms, which exerted synergistic effects of multiplicative proportions on overall QoL. Patients who reported co-occurrence of these symptoms during treatment experienced significantly greater QoL impairment (physical, role and social functioning, fatigue, N&V, appetite loss, overall physical health, overall QOL) and psychological distress (cancer distress, premorbid neuroticism) than those unaffected (0.001 > p ≤ 0.05). Moreover, nausea was more pervasive than vomiting or appetite loss across treatment and had a greater impact on overall QoL. While antiemetic therapy was effective for vomiting and helped prevent/relieve associated appetite loss, the benefits for appetite loss were seemingly constrained by its failure to exert adequate control over nausea in many patients. Conclusions: TIN+/-V still represents a very major concern for patients. Uncontrolled TIN+/-V often results in significant appetite and weight loss, leading to increased risk for malnutrition. Malnutrition and weight loss, in turn, are associated with poorer prognosis, treatment tolerance and response, performance status, QoL and survival. Consequently, a multiple symptom intervention approach focusing on N&V as core symptoms is recommended. Clinicians should genuinely consider combining essential antiemetic therapies with other evidence-based pharmacological (e.g. nausea: psychotropics, such as olanzapine) and non-pharmacological approaches (e.g. N&V: relaxation) in attempts to not only improve prevention and control of N&V for their patients, but also reduce the synergistic impact of cluster symptoms (e.g. N&V, appetite loss) as a whole and resultant QoL impairment likewise. Where associated symptoms are not adequately controlled by these antiemetic-based interventions, targeted evidence-based strategies should be supplemented. © 2012 Springer-Verlag.