Recently, a few studies reported that fatigue was a predominant contributor to patient-perceived overall QoL in patients with different types of cancer in a relatively early stage of disease. In the present study, we aimed to investigate whether fatigue is also a major contributor to overall QoL in preterminal cancer patients. Ninety-eight preterminal cancer patients, mainly lung (44%) and gastrointestinal cancer (25%), with an estimated life expectancy of 1-6 months were included. QoL domains as well as overall QoL were measured using the EORTC QLQ-C30 questionnaire. Data were analysed by Pearson's correlations and multivariate modelling. Fatigue showed the strongest correlation with overall QoL (r = -0.63, p < 0.001), followed in decreasing order by role functioning (r = 0.53), physical functioning (r = 0.47), social functioning (r = 0.44), nausea (r = -0.37), cognitive functioning (r = 0.33), appetite loss (r = -0.31), dyspnea (r = -0.26) and emotional functioning (r = 0.24). Multivariate analysis confirmed that the fatigue scale paid by far the highest individual contribution to overall QoL (standardized regression coefficient (SRC): -0.41, p = 0.002), followed by social functioning (SRC: 0.18, p = 0.05). None of the other domains or symptom scales contributed independently to overall QoL. Our results clearly demonstrate that, in preterminal cancer patients, fatigue is a major contributor of overall QoL, corroborating reports in cancer patients in earlier disease stages.