We conducted a study to evaluate the effectiveness of twelve different similarity measures in matching the corresponding masses on temporal pairs of current and prior mammograms. To perform this comparison we implemented each of the twelve similarity measures in the final stage of our multistage registration technique for automated registration of breast lesions in serial mammograms. The multistage technique consists of three stages. In the first stage an initial fan-shape search region was estimated on the prior mammogram based on the geometrical position of the mass on the current mammogram. In the second stage, the location of the fan-shape region was refined by warping, based on an affine transformation and simplex optimization. A new refined search region was defined on the prior mammogram. In the third stage, a search for the best match between the lesion template from the current mammogram and a structure on the prior mammogram was carried out within the search region. Our data set consisted of 318 temporal pairs. We performed three experiments, using a different subset of the 318 temporal pairs for each experiment. In each experiment we further tested how the performance of the similarity measures varied as the size of the search region increased or decreased. We evaluated the twelve similarity measures based on four criteria. The first criterion was the mean Euclidean distance, which was the average distance of the true location of the mass to the location detected by the similarity measure. The second criterion was the percentage of temporal pairs that were aligned so that 50% or more of the lesion area overlapped. The third criterion was the percentage of pairs that were aligned so that 75% or more of the lesion area overlapped. The fourth and final criterion was the robustness of the similarity measure. Our results showed that three of the similarity measures, Pearson's correlation, the cosine coefficient, and Goodman and Kruskal's Gamma coefficient, provide significantly higher accuracy (p < 0.05) in the task of matching the corresponding masses on serial mammograms than the other nine similarity measures.