The authors have reported previously that conventionally defined grades of tumor morphology do not correlate with tumor response or survival in advanced squamous cell cancers of the head and neck (SCCHN) treated with cisplatinum combination induction therapy. This lack of correlation may be the result of the imprecision and subjectiveness of the conventional grade determination. To examine this possibility, response and survival were correlated with individual parameters of morphologic differentiation in 136 patients with advanced, untreated SCCHN. A multi-variable analysis of degree of keratinization, number of mitotic figures per high powered field, degree of nuclear differentiation, presence of vascular invasion, intensity of inflammatory response, and invasion pattern of the cancer was performed. The grade of each variable was weighted by assigning a score from 1 to 4, with 1 representing the most differentiated and 4 the least. The cumulative score of each specimen was tallied and assigned to one of three groups, less than 12, 12 to 18, and greater than 18, analogous to the conventional grades of well, moderately, and poorly differentiated, respectively. No correlation between the grade of individual morphologic variables and response to chemotherapy was demonstrated, or between tumor response and cumulative score groups. There was no correlation of the grade of individual morphologic variables or cumulative score groups with survival. Only the survival of patients achieving a complete response to chemotherapy was correlated with the cumulative score groups: 2-year survivals of 84%, 70%, and 46% for less than 12, 12 to 18, and greater than 18, respectively. Multi-parameter analysis of individual features of tumor differentiation is not superior to conventional morphologic analysis in predicting response to chemotherapy or survival in patients with advanced SCCHN.