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Objective Despite the remarkable progress in efforts to control disease spread, the nationwide elimination of hepatitis B in China is still hindered by the persistently high rate of hepatitis B virus (HBV) infection in Western China. This study aimed to evaluate the strategy of hepatitis B prevention and control in Western China and identify potential areas and strategies for improvement. Methods Susceptible population vaccination, health education, professional training of doctors, and other prevention and control measures have been implemented in Wuwei city since 2010. Data were obtained from three representative cross-sectional serosurveys conducted in 2010, 2013, and 2015. The serum samples were subjected to enzyme-linked immunosorbent assays to detect the following seromarkers: HBV surface antigen (HBsAg), antibody against hepatitis B surface antigen (anti-HBs), and antibody against hepatitis B core antigen (anti-HBc). Estimates of variance were determined using Taylor series linearization methods. Results The three serosurveys revealed decreases in the prevalence of HBsAg (7.19% in 2010 vs. 6.51% in 2013 vs. 5.87% in 2015) and anti-HBc positivity (43.89% vs. 32.87% vs. 28.46%) and an increase in the prevalence of anti-HBs positivity (49.07% vs. 53.66% vs. 53.72%) over time. From 2010 to 2015, the legally reported incidence of hepatitis B in Wuwei city decreased from 686.53/100,000 to 53.72/100,000. Notably, persistently high HBsAg-positive rates (above 5.40%) were observed among subjects aged 20–69 years old in the three serosurveys; the prevalence of HBsAg was above 1% among children younger than 10 years old. Furthermore, rural subjects had higher rates of HBsAg and anti-HBc positivity than their urban counterparts (6.04% vs. 4.83% and 30.26% vs. 20.35%, respectively) in 2015 but had a lower rate of anti-HBs positivity (49.68 vs. 55.18%). Multivariate regression analysis showed that age, urban and rural areas, and education level were the main factors affecting HBV infection. Conclusion Although vaccine-based prevention and control measures reduced the rate of HBV infection in Wuwei City over time, the hepatitis B infection rate in children younger than 10 years was still higher than the national average level. Therefore, the prevention and control of mother-to-child transmission and the management of the infected should be the focus of future prevention and control work.