Abstract: A one-dose varicella vaccination program for children aged 1-14 years was introduced in Guangzhou in 1999. Since November 2017, a two-dose varicella vaccination program has been implemented, with the first dose for children aged 12-24 months and the second dose for children aged 4-6 years. To evaluate the effectiveness of the two-dose varicella vaccination strategy in Guangzhou, we conducted an interrupted time series (ITS) analysis using monthly reported varicella incidence data (2011-2024) and demographic statistics. In total, 225,497 varicella cases were reported between January 2011 and December 2024. The annual average reported incidence rate from 2011 to 2024 was 106.59 per 100,000. Prior to the two-dose varicella vaccine intervention (2011-2017), the annual average reported incidence rate was 126.80 per 100,000, while the post-intervention (2018-2024) annual average reported incidence rate was 91.14 per 100,000. Varicella cases in Guangzhou exhibited a bimodal distribution, peaking primarily between October and January (accounting for 42.14% of all cases, n=95,023) with a secondary peak in May. For the general population, varicella incidence showed a non-significant pre-intervention increasing trend of 0.3% per month (t = 2.27, P = 0.294). Post-intervention, a significant level change of +7.719 per 100,000 (t = 10.024, P < 0.001) was observed, with a slope change of -2.1% (t = -9.956, P < 0.001). This corresponds to a sustained monthly decline in incidence of 1.8%, indicating a statistically significant long-term reduction. Across age groups, the 4-6-year-old group demonstrated the most substantial decrease (a 3.8% monthly reduction), followed by the 7-9-year-old group. All age groups exhibited statistically significant long-term declining trends. To optimize varicella control, we suggest a phased introduction of the two-dose vaccine into China’s NIP, with Guangzhou as the pilot site focusing on 4-6-year-olds, while assessing the cost-effectiveness to guide future policy.