To evaluate whether there are histopathologic features of negative temporal artery biopsy (TAB) that allow differentiation between patients with giant cell arteritis (GCA) and those without. METHODS: All consecutive patients with negative TAB seen between January 2009 and December 2012 were selected retrospectively. Demographic, clinical, and laboratory data at presentation and at each followup visit were collected. A pathologist with expertise in vasculitis and blinded to clinical data and final diagnosis reviewed all negative TABs. Histopathologic features evaluated were the presence of a focal mediointimal scar, medial attenuation, intimal hyperplasia, fragmentation of inner elastic lamina, calcification, adventitial fibrosis, and neoangiogenesis. RESULTS: After a median (interquartile range [IQR]) followup period of, respectively, 19 months (9.2-31.2) and 26.3 months (4.9-36.7) (P = 0.041), 38 (55%) of 69 patients had a final diagnosis of TAB-negative GCA, while in the remaining 31 (45%) of 69 patients GCA was excluded. The American College of Rheumatology classification criteria for GCA were satisfied by 31 (81.6%) of 38 patients and 2 (6.5%) of 31 patients (P < 0.0001). Compared to non-GCA patients, those with TAB-negative GCA had more frequent cranial manifestations and higher erythrocyte sedimentation rates and C-reactive protein levels. The frequency of patients receiving prednisone, the mean dose, and the duration of prednisone treatment at TAB were similar in the 2 groups. There were no significant differences between TAB-negative GCA and non-GCA patients in the frequencies of all the histologic features evaluated. CONCLUSION: The histologic features of negative TABs evaluated in this study do not allow for the differentiation between GCA and non-GCA patients. In the absence of an inflammatory infiltrate, other histologic changes of the temporal artery wall are not specific for GCA.