Renal transplant recipients have a well-recognized increased risk of de novo neoplasia. In this study, we investigated whether lymphocyte subset count could predict the risk of developing noncutaneous neoplasia (NCSC) in renal transplant recipients (RTR). Between January 1995 and December 1995, lymphocyte subsets (CD4, CD8, CD19) were measured in 281 RTR. This population was studied until November 1999 for the development of NCSC. The mean follow-up was 42+/-9 months. Neoplasm was diagnosed in 22 patients (7.9%). Patients who developed a cancer were significantly older (53.8+/-6 years vs 38+/-16 years, P<0.0001), had lower CD4 (234+/-126/mm(3) vs 543+/-214/mm(3), P<0.005) and CD19 (19+/-9/mm(3) vs 51+/-22/mm(3), P<0.0001) levels, and more frequently had past histories of skin cancer (24% vs 4%, P<0.01). Cox regression revealed that high CD4 levels (RR 0.73, 95% CI 0.62-0.89 for each 100/mm(3) increase in CD4 cell count) were associated with decreased risk of NCSC, whereas age (RR 2.49, 95% CI 1.12-5.92 for each 10-year increase in age) was predictive of the subsequent development of NCSC. To conclude, CD4 cell depletion is associated with the development of solid cancers and lymphoma in RTR.