Ultraviolet (UV) radiation is a prevailing factor implicated in the etiology of keratinocytic intraepidermal neoplasia (KIN) and squamous cell carcinomas (SCCs), as evidenced by the high frequency of UV-related mutations in the p53 and p16 tumor suppressor genes. In renal transplant recipients (RTRs), immunosuppression is considered another important risk factor in the enhanced carcinogenesis in these patients. So far, effects of UV and immune status on p53 and p16 immunoexpression in SCCs and precursors have not been studied. The aims of this study were to assess (1) the relation between risk factors for carcinogenesis, sun exposure and immune status, and p16 or p53 expression, and (2) to assess differences in p16 and p53 expression between KINs and SCCs. Immunostaining for p16 and p53 was performed on paraffin-embedded sections of 23 low-grade KIN (LKIN) lesions, 28 high-grade KINs (HKINs), and 35 SCCs from 44 RTRs and 42 immunocompetent controls (ICIs). In 74/86 lesions (86%), p53 was expressed, and in 63/86 (76%) lesions, p16 expression was present. Negativity for both p16 and p53 was found in 4/86 (5%) cases, whereas combined p53/p16 staining was most prevalent (55/86 lesions, 64%). P16 staining proved independent of p53 expression (P =.8), and immune status, sun exposure, and histological diagnosis (LKIN-HKIN-SCC) had no influence on this independence. Transplantation was associated with p53 expression in SCCs (P =.02; power = 34%) caused by higher prevalence of p53-negative SCCs in RTRs than in ICIs (30% versus 0). In HKINs, p16 was more frequently positive than in LKINs (P =.003; power = 49%) and SCCs (P =.03; power = 53%). HKINs showed more frequent transepidermal p16 and p53 staining than LKIN lesions (P <.001; power >/= 99%). This study demonstrates that in KIN lesions and cutaneous SCCs, p16 expression is independent of p53 expression, and immune status, sun exposure, and histological diagnosis have no influence on this independence. Furthermore, HKIN lesions express significantly more p16 than LKINs and SCCs.