Acute rhinosinusitis (ARS) is a very common/disease faced more often by general practitioners than ear, nose and throat specialists, pneumologists or allergologists. In an outpatients setting, upper respiratory tract infection is the third most common cause of a primary care consultation, one third of which is attributable to ARS, diagnosed upon clinical presentation. In some cases however, signs and symptoms do not allow clear differentiation from viral, post-viral or bacterial infection. This compels GPs and family doctors to make a careful choice and first use the best antimicrobial treatment to avoid recurrences or complications and the rise of antibiotic resistance. Amoxicillin, thanks to its narrow spectrum against likely respiratory pathogens, is recommended as first-line therapy to treat acute bacterial rhinosinusitis by several international guidelines, being safe at the same time. Other antibiotics (beta-lactams, macrolides and newer drugs, such as fluoroquinolones) have been evaluated in double-blind studies versus placebo or comparative studies in terms of efficacy, safety and costs. Prulifloxacin, the active metabolite of ulifloxacin, is an oral fluoroquinolone with a broad in vitro activity spectrum against Gram positive and negative bacteria and among fluoroquinolones has the lowest power of inducing resistance. In vitro and in vivo studies have shown its clinical efficacy and pathogen eradication. Ulifloxacin T(1/2) and plasma and tissue concentrations including the nose-paranasal sinuses mucosa allow once daily administration at the dosage of 600 mg. Prulifloxacin shows a high safety profile: it is the fluoroquinolone with the lowest risk of cardiac arrhythmias for prolongation of the QT interval; the CNS penetration is negligible; in women prulifloxacin does not affect the lactobacillary component of the vaginal microbiota, lowering the risk of genito-urinary tract infections. The pharmacokinetic characteristics and safety profile of prulifloxacin make it the antibiotic option with the best potential to achieve clinical cures and bacteriological eradication, well tolerated and safe without specific restriction or posologic changes in the elderly and in patients with co-morbidities in multiple treatment, hence resolving ARS reliably and being simple and easy to administer.