BACKGROUND: Patients with non-Hodgkin's lymphoma (NHL) are at increased risk for second cancers. Few studies, however, include long-term survivors, and none report risk for second cancer among NHL patients surviving 15 or more years. PURPOSE: Our aim was to examine the pattern of second cancers among long-term survivors of NHL. METHODS: A cohort of 6171 patients diagnosed with NHL as a first primary cancer and who survived 2 or more years was identified within population-based tumor registries in Sweden, Ontario, and Iowa and within the affiliated tumor registry of The Netherlands Cancer Institute. Nearly 1000 NHL patients lived 15 or more years after diagnosis. Tumor registry files were searched for new invasive primary malignancies. RESULTS: Second cancers were reported in 541 subjects (observed-to-expected ratio [O/E] = 1.37; 95% confidence interval = 1.26-1.49), with significant excesses seen for all solid tumors (O/E = 1.28), acute nonlymphocytic leukemia (O/E = 4.83), melanoma (O/E = 2.38), Hodgkin's disease (O/E = 12.0), and cancers of the lung (O/E = 1.36), brain (O/E = 2.33), kidney (O/E = 2.07), and bladder (O/E = 1.77). Among 15-year survivors, significantly increased risks persisted for all second cancers (O/E = 1.45), solid tumors (O/E = 1.37), bladder cancer (O/E = 3.24), and Hodgkin's disease (O/E = 25.0). The actuarial risk of developing a second cancer 3-20 years after diagnosis of NHL was 21%, compared with a population expected cumulative risk of 15%. CONCLUSIONS: Patients with NHL continue to be at significantly elevated risk of second primary cancer for up to two decades following diagnosis. The pattern of risk suggests the influence of treatment as well as factors associated with the underlying disease. IMPLICATIONS: Quantitative studies of second cancer following NHL are needed to clarify the role of antecedent therapy, shared risk factors, host susceptibility, and other etiologic and diagnostic influences. Despite the generally advanced age of patients with NHL, the persistently elevated risk of second cancers should alert clinicians to the importance of continued medical surveillance.