Introduction/Objective Lyme borreliosis is a multisystem infectious disease caused by Borrelia burgdorferi spirochetes transmitted by the bite of an infected tick. The disease manifestations are very different, with the skin, joints, heart, and nervous systems being most often affected. The aim of this study was to find out whether there are significant differences in the appearance of symptoms and signs of the disease between the subjects who did / did not receive prophylactic, early antibiotic therapy, after the tick bite in patients diagnosed with the early phase of Lyme borreliosis. Methods The study was carried out on 2,070 patients, who were treated or examined at the Clinic for Infectious and Tropical Diseases in the 1989-2004 period. The patients were divided into group A (n = 591), in which they were given early antibiotic therapy, and group B (n = 1,479), in which they were not. The antibiotic therapy was used within five days of a tick bite in patients with a probable infection, who, at the time, did not have any symptoms or signs. The applied antibiotics included cephalosporins, macrolides, tetracyclines, semisynthetic penicillins, repeatedly for seven or 14 days, or benzathine benzylpenicillin once only. Results The disease developed in a statistically significantly larger number of patients who were not given early antibiotic therapy (537/1,479) than in those who received the therapy (10/951), i.e. the ratio was 36.3% vs. 1.7%. We concluded that only two antibiotics were sufficient for optimal prevention: doxycycline and ampicillin, administered for seven days. The applied antibiotics showed a high statistically significant efficacy, ranging from 93.7% (cephalosporins) to 99.4% (macrolides). Conclusion The application of early antibiotic therapy after a tick bite was effective in preventing the early phase of Lyme borreliosis, while in the case of infection it prevented the development of extracutaneous manifestations.