The purpose of this article is to report on the study of the psychometric properties of the European Portuguese version of the World Health Organization Quality of Life Questionnaire--WHOQOL-100, in a clinical sample of patients with bone and soft tissue cancer. Eighty-one participants, in different phases of the disease, were recruited from the Department of Orthopaedics of the Coimbra University Hospitals. After the informed consent was obtained, all patients responded to the European Portuguese version of WHOQOL-100 and the Portuguese versions of Beck Depression Inventory (BDI) and Brief Symptoms Inventory (BSI). The results show an acceptable internal consistency for the set of facets, domains, and 100 questions (alphas from 0.73 to 0.96) and across domains (alphas from 0.82 to 0.94), as well as an acceptable test-retest reliability (test-retest correlations from 0.71 to 0.88) of WHOQOL-100. Construct validity was demonstrated by moderate correlations between domains (r from 0.23 to 0.70) and with the general facet (r from 0.32 to 0.57), concurrent validity by its correlation with the total scores of BDI and Global Severity Index of BSI, and discriminant validity by its ability to discriminate between healthy individuals and cancer patients. In general, the European Portuguese version of WHOQOL-100 is a reliable and valid instrument for the assessment of quality of life in patients with bone and soft tissue cancer.