Antimicrobial peptides (AMPs) are one of the primary mechanisms used by the skin in the early stages of immune defense. AMPs have a broad antibacterial activity and also show antifungal and antiviral attributes. Various studies have also shown that levels of antimicrobial peptides change with the development of neoplasia. The aim of this paper is to assess the associations between the presence of basal cell carcinoma (BCC) and the plasma concentrations of cathelicidin and β-defensins (HBD1-3). We examined 108 patients (56 women, 52 men). The BCC group consisted of 49 patients with mean age 69.8 ±12.3 and the control group consisted of 59 participants with mean age 62.1 ±11.1. A statistical analysis of data was performed. The median serum concentration of cathelicidin was almost 3 times higher and the median concentration of HBD-2 more than 6 times higher in BCC patients than in the control group (p < 0.001). The logistic regression model revealed in univariate analysis that patients who had a detected cathelicidin level above ~1500 pg/ml had 9.9× higher likelihood of having BCC identified in the histopathology in comparison with the control group. In patients who had a HBD-2 level above ~1.2 ng/ml the OR of having BCC identified in the histopathology was 12.6 (p < 0.001). Elevated concentrations of cathelicidin and β-defensin 2 are associated with the presence of basal cell carcinoma. Additionally, the specificity of cathelicidin and β-defensin 2 in detecting basal cell carcinoma is high. However, it should be remembered that these factors are not specific only to this condition and further studies are needed.