BACKGROUND: The Immune Defence trial documented a short-term impact on respiratory tract infections (RTIs) for nasal sprays and a stress management and physical activity website. AIM: To estimate the impact of sprays and the website after 12 months. DESIGN AND SETTING: A four-arm parallel randomised controlled trial. Participants with comorbidities and/or ≥3 self-reported recurrent RTIs were recruited. METHOD: Participants were randomised by online software (stratified by recurrent illness and comorbidities) to a) usual care (n = 3451); b) Vicks First Defence (VFD) spray (n = 3448) (two sprays/nostril, ≤6 times a day; c) isotonic saline spray (n = 3450) (same dosing); or d) a website promoting physical activity and stress management (n = 3450). The primary outcome was respiratory illness days. RESULTS: Usual care participants (n = 3052) had on average 21.8 (standard deviation [SD] 35.2) illness days, reduced by VFD (n = 3076; 17.8 [SD 27.9] days, adjusted incidence rate ratio [IRR] 0.84, 99% confidence interval [CI] = 0.79 to 0.90, P<0.0001), and saline (n = 3142; 17.7 [SD 21.1 ] days, IRR 0.83, 99% CI = 0.78 to 0.89, P<0.0001), but not the website (n = 2811; 19.5 [SD 31.2] days, IRR 0.94, 99% CI = 0.88 to 1.01, P = 0.03). The website reduced incident infections (adjusted risk ratio [RR] 0.96, 95% CI = 0.93 to 0.99, P = 0.006). All interventions reduced symptom severity and work days lost, both spray groups reported lower intention to consult and fewer falls, and there were fewer antibiotic courses and practice visits with saline. Among those with recurrent illness, saline had the most impact on both recurrence and symptom days (RR 0.93, 95% CI = 0.87 to 0.99 and RR 0.70, 95% CI = 0.60 to 0.82, respectively). Headaches were higher for VFD and lower for saline (7.8% and 3.4%, respectively; 4.7% usual care). CONCLUSION: Widely available, inexpensive sprays and a website promoting self-care reduce the incidence, duration, and/or severity of RTIs and have an impact on work days lost and healthcare use.