Background: Reports to date have provided widely divergent estimates of the risk of second malignant neoplasms in patients with chronic lymphocytic leukemia (CLL), ranging from cancer deficits to excesses of twofold to threefold. Purpose: Our purpose was to estimate the risk of second primary cancers following CLL, utilizing population-based tumor registries, and to determine whether site-specific excesses might be associated with type of initial treatment for CLL. Methods: We analyzed data for 9456 patients diagnosed with CLL as a first primary cancer between 1973 and 1988, who were reported to one of nine tumor registries participating in the National Cancer Institute‘s Surveillance, Epidemiology, and End Results(SEER) program and who survived 2 or more months. SEER files malignancies that developed at least 2 moths after the initial CLL diagnosis. Results: Compared with the general population, CCL patients demonstrated a significantly in creased risk of developing all second cancers (840 observed; observed-to-expected ratio[O/E]=1.28; 95% confidence interval [CI]=1.19–1.37). Significant excesses were noted for cancers of the lung (O/E=1.90), brain(O/E=1.98), and eye (interaocular melanoma) (O/E=3.97) as well as malignant melanoma (O/E=2.79) and Hodgkins disease (O/E=7.69).Cancer risk, which did not vary according to initial treatment category was also constant across all time intervals after CLL diagnosis. Conclusion: CLL patients are at a significantly increased risk of developing a second malignant neoplasm. The patern of cancer excesses suggests a susceptibility state permitting the development of selected second malignancies in patients with CLL, perhaps because of shared etiologic factors, immunologic impairmentm, and /or other influences. Although our results fo not suggest a strong treatment effect, more detailed studies of second tumors in CLL are needed to investigate the role of radiation therapy and chemotherapy. [J Natl Cancer Inst 84: 1422–1427, 1922]