We developed a tool that performs longitudinal subtraction of 3D double inversion recovery (DIR) images in follow-up magnetic resonance (MR) examinations of patients with multiple sclerosis. As DIR sequences show a high lesion-to-parenchyma contrast, we hypothesized that such a tool might lead to increased sensitivity for new lesions as well as to speeding up the routine clinical work-up of follow-up MR imaging in multiple sclerosis by directly visualizing new lesions. DIR subtraction images of serial MR examinations were calculated in 106 patients with multiple sclerosis. Existence of new lesions was assessed in three different ways: by standard visual comparison, by FLAIR, and by DIR subtraction maps. A reference standard, to which the single modalities were compared, was defined by combining all information from all readouts and all readers. The presence and number of new lesions were determined and the time needed for analysis measured. Accuracy of detecting overall existence of new lesions using DIR subtraction maps was significantly higher than using visual comparison (96 vs. 86%, p = 0.013) or FLAIR subtraction maps (p < 0.001), with increased sensitivity and higher negative predictive value. Significantly more new lesions were detected when using DIR subtraction maps (p < 0.001). Analyzing subtraction maps took less than a third of the time needed for the standard visual comparison (p = 0.007). Thus, DIR subtraction maps improve the detection of new lesions in a clinical setting both in terms of accuracy and in terms of speed.