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The genetic factors that mediate the pathogenesis of multiple primary cutaneous basal cell carcinomas (BCC) are largely unclear. Thus, some patients suffer many BCC (>30) and/or rapid accrual (number of tumours/year from first presentation) of further lesions. We have studied, in 827 English Caucasians, the influence of polymorphism in carcinogen-metabolizing enzymes on susceptibility to this cancer. Accordingly, we describe, first, a cross-sectional analysis of the influence of GSTM1, GSTT1, CYP2D6 and CYP1A1 genotypes on tumour numbers, and secondly, a longitudinal analysis, in 169 of these cases, of the effect of these genes on tumour accrual. We have confirmed the expected importance of age and number of lesions at presentation, and male gender and skin type as risk factors. Furthermore, the cross-sectional analysis showed CYP1A1 m1m1 (P = 0.004; rate ratio 1.242) and CYP2D6 EM (P < 0.001, rate ratio 1.266) are associated with increased numbers of BCC. The longitudinal study showed, after adjustment for age and tumour number at presentation, that GSTT1 null (P < 0.001, rate ratio 2.677) and CYP2D6 EM (P < 0.001, rate ratio 2.154) were significant determinants of accrual while CYP1A1 Ile/Ile was associated with slower accrual than the Ile/Val and Val/Val genotypes (P = 0.008, rate ratio 0.690). We believe these are the first genetic factors to be associated with tumour accrual. No significant interactions between genotypes were identified, though the combinations GSTM1 null/skin type 1 (P < 0.001, rate ratio 2.702), CYP2D6 EM/male gender (P = 0.049, rate ratio 1.279) and CYP2D6 EM/blue+green eyes (P = 0.046, rate ratio 1.388) influenced tumour numbers. Previous studies indicate the importance of effective repair of UV-damaged DNA in the pathogenesis of multiple BCC; indeed the influence of GSTM1 may result from its ability to utilize 5'-hydroxymethyluracil. However, the finding that CYP2D6 and CYP1A1 influence tumour numbers and accrual indicates detoxification of unknown molecules is important and supports the view that factors other than UV are important in the pathogenesis BCC.