With the development of new treatment strategies, the survival of CLL patients has improved. Some reports indicate that CLL patients may be at increased risk of subsequent cancer. Patterns for the specific type of cancer may provide insights into possible causes associated with the development of secondary cancers. We evaluated the development of second cancer after diagnosis with CLL among 1069 patients diagnosed at M. D. Anderson Cancer Center between 1985 and 2001. Only patients with no prior invasive cancer and were followed-up for at least 1 year were included in the analysis. The mean age was 56 years (range: 16–89 years) and the male-to-female ratio was 1.47. During the mean follow-up of 6 years (range: 1–20 years), sixty six (6%) patients were diagnosed with secondary invasive cancers: breast (12), lung (11), colorectal (7), prostate (7), melanomas (6), Hodgkin’s disease (HD) (5), acute myelogenous leukemias (AML) (3), bladder cancers (3), myelodysplastic syndromes (MDS) (3), Merkel cell carcinomas (2), pancreatic (2), esophageal cancer (1), kidney (1), liver (1), endometrial (1) and appendix (1). The mean time to the development of secondary cancers was 4.7 years (range: 1 – 16 years). We compared the observed number (O) of second cancers to the expected number (E) calculated from the age-, sex- and calendar-year matched general US population using the Connecticut Tumor Registry data. Overall, no excess of second cancers was found, the standard incidence ratio (SIR) [O/E = 66/62 = 1.07 (95% CI: 0.84 – 1.37)]. When stratified by treatment, no significant increased risk of second cancer was observed among treated (SIR = 36/35.6 = 1.01, 95% CI: 0.71 – 1.40) and untreated patients (SIR = 30/25 = 1.20, 95% CI: 0.81 – 1.72) compared to the general population. However, when analyzing risks by cancer sites, higher risk of secondary melanoma (SIR = 4/0.85 = 4.71, 95% CI: 1.28 – 12.1) was observed among patients diagnosed with CLL at age older than 60 years. All five secondary Hodgkin’s disease were diagnosed in men, a significant excess of HD was found among both older (≥ 60 years) (SIR = 3/0.13 = 23.1, 95% CI: 4.75 – 67.4) and younger patients (< 60 years) (SIR = 2/0.15 = 13.3, 95% CI: (1.61 – 48.1). All three patients diagnosed with AML were men, and they had higher risk of developing AML (SIR = 3/0.33 = 9.09, 95% CI: 1.87 – 26.5). Two out of three patients who developed AML were treated with alkylating agents. Patients who received chemotherapy for CLL had an increased risk of developing AML (SIR = 3/0.27 = 11.1, 95% CI: 2.29 – 32.4) and HD (SIR = 4/0.16 = 25.0, 95% CI: 6.8 – 64.0). However, no increased risk of AML was found among those who received fludarabine alone and those never received any treatment for CLL. This large study confirmed that site-specific excesses of second cancers after CLL diagnosis did exist. The excess of AML among those treated with chemotherapy may due to alkylating agents. Monotherapy with new purine analog drug did not increase the risk of AML in this study. Further research is needed to investigate the causal relationship between CLL and second malignancies.