The combination of oral clindamycin with rifampicin is recommended by European guidelines as a first‐line treatment in moderate‐to‐severe hidradenitis suppurativa (HS). Recent studies highlight that oral clindamycin in monotherapy (CM) may be a useful alternative treatment. We included 36 patients with a diagnosis of moderate‐to‐severe HS. A total of 19 patients were treated with combination oral clindamycin plus rifampicin (C + R) and 17 with oral CM for 12 weeks. The efficacy of CM vs C + R was analyzed by multilinear regression models which showed a higher reduction in mSartorius (Δ = −13.2, P = .058) and AISI (Δ = −4.91, P = .034) in the C + R group. In the C + R group, smoking pack‐year was positively correlated with AISI (Spearman's rho = 0.51, P = .036) and with DLQI (0.47, P = .061). In the CM group, a positive correlation was found between BMI and AISI (0.47, P = .041). The data on the efficacy of C + R combination therapy are in line with guidelines, evidence‐based approaches, and recommendations from the HS ALLIANCE working group. The rationale for combining these two drugs is to increase bactericidal action and to reduce rifampicin resistance, as rifampicin is highly mutagenic. Our results suggest that the antibiotic combination of C + R is still the treatment of choice in moderate‐to‐severe HS with abscesses, draining fistulae and ≥ 5 inflammatory nodules. High BMI and smoking habits seem to be predictive factors of a poor response to antibiotics. Further multicenter studies and prospective randomized controlled trials are needed to confirm these results. Potential alternative antibiotic therapies should also be investigated.