Among 191 chronic lymphocytic leukemia (CLL) patients seen at our institution over an 18-year period, 13 (6.8%) were found to have a second neoplasm (sN). A neoplasm associated with CLL was diagnosed concurrently in 7 cases and subsequently in 6, respectively. Although a trend toward a more frequent incidence in male patients older than 65 years with a more aggressive form of leukemia and who needed therapy could be detected, the clinical characteristics of these 13 patients did not differ significantly from those of the general population of CLL patients. The analysis of the sN risk as a function of the length of follow-up, by calculating the actuarial risk and the hazard function plot, provides important information on the natural history of sN appearing in CLL. The actuarial risk of sN at 5 years was 9.7% or 6.9%, respectively, according to whether we did or did not consider cases of cutaneous carcinomas. The smoothed hazard function showed a pattern of decreasing rate over the first year, a rise to 3.0% by the third year, and no increasing risk later in the follow-up. This trend was associated with a high incidence of sNs synchronous with CLL, and with a clustering of sNs among patients who died early, before reaching median survival. In addition, the early appearance of the sN risk is analogous to the renal transplant experience and suggests that sNs may result from impaired immune surveillance.