Incidence of lip cancer is markedly increased after kidney transplantation. Immunosuppression and other risk factors for lip cancer were investigated in a population-based, nationwide cohort of 8,162 kidney transplant recipients registered on the Australia and New Zealand Dialysis and Transplant Registry (1982-2003). Lip cancer diagnoses were ascertained using probabilistic data linkage with the Australian National Cancer Statistics Clearing House. Standardized incidence ratios were used to compare lip cancer risk by subsite of lip and during periods of transplant function and failure. Risk factors during the first functioning transplant were examined using multivariate Poisson regression. Lip cancer was diagnosed in 203 patients. All cases were of squamous cell origin and mostly (77%) affected the lower vermillion. Cases occurred predominantly during periods of transplant function, with incidence decreasing to pretransplantation level on transplant failure and cessation of immunosuppression. During transplant function, cancer of the lower vermillion was associated with increasing year of age [incidence rate ratio (IRR), 1.03; 95% confidence interval (95% CI), 1.02-1.05], greater time since transplantation (P < 0.001), smoking (IRR, 2.13; 95% CI, 1.12-4.07), and current use of azathioprine (IRR, 2.67; 95% CI, 1.39-5.15) or cyclosporine (IRR, 1.63; 95% CI, 1.00-2.65). Female sex (IRR, 0.29; 95% CI, 0.18-0.46) and non-Australian/New Zealand country of birth (P = 0.006), surrogate indices of reduced exposure to solar UV radiation, were significantly protective. Lip cancer after transplantation is strongly related to the current receipt of immunosuppression. During transplant function, lip cancer risk is associated with the duration of immunosuppression, receipt of specific immunosuppressive agents, and UV exposure.