Aim: To evaluate the clinical efficacy of tetracycline, doxycycline, and lymecycline in patients with hidradenitis suppurativa (HS). Methods: A prospective study of three different treatment regimens in patients with HS; oral tetracycline 500 mg twice daily, oral doxycycline 100 mg twice daily, and oral lymecycline 300 mg twice daily were administered in patients with HS. Outcomes were change in Hidradenitis Suppurativa Score (HSS), Dermatology Life Quality Life index (DLQI), overall disease-related distress, boil-related pain, number of boils in the preceding month, fraction of patients with no boils in the preceding month, and Physician's Global Assessment (PGA) score at follow-up. Results: In total, 108 patients, 73 (67.6%) women and 35 (32.4%) men, were included. Mean duration of treatment was 4.3 months. The mean HSS at baseline was 26.10 (SD 20.18) points, improving to 17.97 (SD 17.88) at follow-up, difference is 8.13 (95% CI 5.21–10.93), P < 0.0001. Highest improvement in HSS was observed in the tetracycline group. After multivariate adjustment, higher reduction in HSS was significantly associated with lower BMI, Hurley stage III, higher HSS at baseline, and higher number of boils in the preceding month at baseline. Conclusion: Oral treatment with tetracycline, doxycycline, and lymecycline appears effective and safe in HS patients. Tetracycline provided the greatest clinical improvement measured by HSS.