Background: The FACT-G has gone through many validation studies. However, little research has been conducted in South American Spanish speaking patients. The present study aimed to evaluate the FACT-G Spanish Version 4 in Uruguayan cancer patients. Methods: The data analyzed were collected from 309 patients, with various tumor sites, at different stages of disease and receiving different treatments. Results: Reliability was evaluated using Cronbach's coefficient alpha and showed high internal consistency for each of the subscales and its total scale (range = .78 - .91) of the FACT-G. The FACT-G total score also showed significant mean differences among known groups (performance status, in vs. outpatients) when tested by ANOVA and t-test. When the tumor stage (Local and Regional vs. Metastatic disease) was used as a clinical anchor, the FACT-G total score, the Physical Well-being (PWB), and Functional Well-being (FWB) subscale scores showed mean differences, ranging from 5 to 10 points in a scale from 0-108 (effect sizes = 0.30-0.60). Item response theory (IRT)-based evaluation using mean square fit statistics (.60-1.4) criteria showed that only two items misfit: "Estoy satisfecho(a) con mi vida sexual" (I am satisfied with my sex life) and "Estoy satisfecho(a) de cómo estoy enfrentando mi enfermedad" (I am satisfied with how I am coping with my illness). Conclusion: The results indicated that, using both traditional and IRT approaches, the Spanish FACT-G has good reliability and validity to be used as a QOL instrument among Uruguayan cancer patients.