Oral and oropharyngeal tumor resection may be associated with disfigurement and dysfunctions that affect essential domains of life. This study aimed at assessing the immediate impact of primary surgery on the health-related quality of life for these patients. Forty-seven patients with squamous cell carcinoma of the lips, oral cavity, or oropharynx, and undergoing treatment in the head and neck surgery center of a large general hospital in the city of São Paulo, Brazil, from October 2005 to September 2006, completed the University of Washington Quality of Life questionnaire pre- and postoperatively (before hospital discharge). A paired t test evaluated differences between assessments; Poisson regression estimated ratios of ratings attributed to each domain (pain, appearance, activity, recreation, swallowing, chewing, speech, shoulder pain, taste, saliva, mood, and anxiety) per patient stratified by sociodemographic, clinical, and behavioral characteristics. The immediate impact of surgery on health-related quality of life corresponded to a 31.1% reduction in the overall rating. The most affected domains were chewing (-73.5%), taste (-61.4%), swallowing (-57.3%), speech (-46.0%), and pain (-42.3%). Anxiety (+65.5%) was the sole domain that improved immediately after surgery. Comparisons involving subgroups of patients indicated that different clinical conditions (regional metastasis, tumor size, and location) were not associated with discrepant health-related quality of life immediately after surgery. The routine pre- and postoperative assessment of health-related quality of life may contribute to evaluate treatment effectiveness, which would otherwise rely exclusively on assessing end-point results such as survival and tumor relapse. This information is relevant to attenuate the prejudicial impact of surgery on the physical and psychosocial functioning of patients.