An increased development of malignancies has been related to modern potent antirejection drugs. The purpose of this retrospective study was to assess the incidence and risk factors for invasive malignancies among 2753 kidney recipients (KRs), who were transplanted in two periods within our 39-year experience; before (group I) versus after (group II) the introduction of calcineurin inhibitors (CNIs). In group I, formed by 703 KRs under conventional therapy, 45 (6.4%) patients developed a malignancy, while in group II, treated with CNIs, of over 2050 KRs, 182 (8.9%) developed a malignancy different from noninvasive skin cancer. The incidence of malignancies was higher in the group of patients treated with CNIs (8.9% vs 6.4%), despite the shorter follow-up period. Moreover, the malignancy was more precocious in the CNI group, namely a mean time of onset of 75 versus 154 months in the conventionally treated group. The older mean age of recipients in group II affected by malignancies (43.6 years vs 34.6 years of the group I) played a significant (P < .001) role when associated with the more powerful immunosuppressive effect of CNIs, while recipient gender, dialysis period, donor source, and retransplants seemed to have few effects on malignancy development. Recipients over 60 under CNIs showed a 21% incidence of malignancies.