Objective The purpose of this study was to characterize the biologic determinants that affect the behavior and management of infiltrating lobular cancer. Methods A prospectively accrued data base containing 1548 breast cancer cases was queried for specific pathologic and mammographic features. From this data base, 777 patients treated and followed-up at the H. Lee Moffitt Cancer Center were reviewed, and comparisons were made between the following three histologic subgroups : 661 infiltrating ductal (ID), 42 infiltrating ductal plus infiltrating lobular (ID + IL), and 74 infiltrating lobular (IL). Results Comparisons of the three histologic forms of breast cancer demonstrated the following : 1. At diagnosis, tumors with IL components were larger than those with ID components (p < 0.001) ; in addition, a greater percentage of IL cancers were T3 lesions (14.8%), compared with ID cancers (4.5%). 2. Sizes of IL tumors were underestimated frequently by mammographic examinations when compared with pathologic measurements (p < 0.001). 3. By comparison to ID tumors, increasing IL tumor size is less likely to be associated with an increased number of metastatic lymph nodes per patient (p = 0.09). 4. Infiltrating lobular cancers treated by lumpectomy with cytologic surgical margin analysis more often gave false-negative results than did ID cancers (p < 0.001). 5. Infiltrating lobular cancers treated by lumpectomy required conversion to mastectomy over 2 times more frequently than ID cancers treated by lumpectomy. 6. Mastectomy was performed more frequently than lumpectomy for the treatment of IL versus ID tumors (p = 0.039). Conclusions Infiltrating lobular cancers are biologically distinct from ID cancers. Although lumpectomy may be performed safely in selected patients, multiple difficulties exist in the management of IL cancer, particularly when breast conservation is chosen.