Significant loss of body weight (SLW) by patients treated for squamous cell carcinomas of the oral cavity and oropharynx (OSCC) may affect treatment completion and results. We assessed factors predicting SLW and its correlation with disease-free survival (DFS) in these patients. We evaluated 226 consecutive patients with previously untreated, operable OSCC whose body weight was recorded before, during, and for up to 1 year after treatment. SLW was defined as ≥10% reduction in pretreatment body weight. Clinicopathologic parameters were compared in patients with and without SLW. Of the 226 patients, 94 (41.6%) experienced SLW and 132 (58.4%) did not. Univariate analyses showed that factors significantly associated with SLW included T3-4, N+, stage III-IV, and oropharyngeal tumors, nonsurgical (radiotherapy or chemotherapy) vs. surgical treatment, posttreatment recurrence, histologic differentiation, involved resection margin, and number of metastatic lymph nodes (pLNs) ≥ 3 (P < 0.05). Multivariate analyses showed that radiotherapy, recurrence, and number of pLNs were significant independent predictors of SLW (P < 0.005). DFS rate was significantly higher in patients without than with SLW (P < 0.01). OSCC patients with multiple pLNs, those undergoing radiotherapy, and those with posttreatment recurrences may require close nutritional monitoring and support.