Background: Nicotine replacement therapy (NRT) was licensed for harm reduction in the United Kingdom in 2005, and guidance to UK Stop-Smoking Services (SSS) to include long-term partial or complete substitution of cigarettes with NRT was issued in 2013. Yet, NRT prevalence data and data on changes in biomarkers associated with long-term NRT use among SSS clients are scarce. Methods: SSS clients abstinent 4 weeks postquit date were followed up at 12 months. At baseline standard sociodemographic, smoking and SSS use characteristics were collected and of those eligible, 60.6% (1047/1728) provided data on smoking status and NRT use at follow-up. A subsample also provided saliva samples at baseline and of those eligible, 36.2% (258/712) provided follow-up samples. Saliva was analyzed for cotinine (a metabolite of nicotine) and alpha-amylase (a stress biomarker). Results: Among those who had used NRT during their initial quit attempt (61.5%, 95% CI 58.4%–64.6%), 6.0% (95% CI 4.3%–8.3%) were still using NRT at 1 year, significantly more ex-smokers than relapsed smokers (9.5% vs. 3.7%; p = .005). In adjusted analysis, NRT use interacted with smoking status to determine change in cotinine, but not alpha-amylase, levels (Wald χ2 (1) = 13.0, p < .001): cotinine levels remained unchanged in relapsed smokers and ex-smokers with long-term NRT use but decreased in ex-smokers without long-term NRT use. Conclusions: Long-term NRT use is uncommon in SSS clients, particularly among relapsed smokers. Its use is associated with continued high intake of nicotine among ex-smokers but does not increase nicotine intake in smokers. It does not appear to affect stress response. Implications: Little is known about the long-term effects of NRT. Given an increasing shift towards harm reduction in tobacco control, reducing the harm from combustible products by partial or complete substitution with noncombustible products, more data on long-term use are needed. This study shows that in the context of SSS, clients rarely use products for up to a year and that NRT use does not affect users’ stress response. Ex-smokers using NRT long-term can completely replace nicotine from cigarettes with nicotine from NRT; long-term NRT use by continuing smokers does not increase nicotine intake. Long-term NRT appears to be a safe and effective way to reduce exposure to combustible nicotine.