Background Endoscopic sinus surgery (ESS) is commonly indicated in the treatment of chronic rhinosinusitis (CRS) yet much is unknown regarding optimum peri-operative care, including with regards to antibiotic prophylaxis. Accordingly, survey data indicate a variation in practice across surgeons. We aimed to study the effects of antibiotic prophylaxis after ESS in greater detail. Methods We report a prospective, multi-centre, randomised, double-blind, placebo-controlled trial assessing oral doxycycline post-ESS in the treatment of bilateral primary CRS. 50 patients were randomised. Symptom scores, demographic data and Lund-Mackay scores were collected as well as endoscopy scores and swab samples for immunoassay and microbiome analysis. Three post-operative timepoints were assessed through to 12 months of follow-up. Results The mean SNOT-22 score at 12 months was significantly worse in the doxycycline group compared to the placebo group (28 v. 13, p=0.03). There was a significant increase in bacterial diversity after ESS. There was a significant yet transient increase in some immune mediators (IL-6, IL-10, TNF-alpha) after surgery but no difference between the immune profile of the two treatment groups. There was no significant difference in endoscopic scores between the treatment groups, when scored, 3 months after surgery. Conclusions In this study, the use of doxycycline after ESS was associated with a worse long-term outcome. This may be due to a deleterious effect on the microbiome which increases in diversity during recovery. Although we have only studied a single antibiotic, we would suggest caution with the use of antibiotic prophylaxis after ESS.