OBJECTIVES Policymakers may have a concern that a long time interval between two doses, partial efficacy and potential waning after the first dose of varicella vaccination would reduce the impact of a universal childhood varicella immunization program. The objective of this study is to determine the potential impact and relative weight of 2 key factors: (1) coverage and (2) vaccine efficacy (VE) of the first dose of varicella vaccination (VE-D1) in the context of long term interval between two doses on varicella epidemiology in Italy. METHODS An age-structured dynamic transmission model is adapted and fitted to the seroprevalence of varicella in Italy in absence of vaccination. Vaccination is introduced with 1- and 2-dose VE, with long time interval between 2 doses (given at 13 months and 6 years of age). Several scenarios are tested including 2 levels of VE-D1 (65%/75%) and 3 coverage levels (95%/80%, 85%/70%, 75%/60%, respectively). Efficacy post-dose 2 is fixed at 95%. RESULTS When considering a long term interval between two doses and for a vaccine coverage of 95%/80%, the reduction in number of varicella cases compared with the absence of vaccination for 75% and 65% VE-D1 was respectively 88.6%/85.9% by year 30, and 79.3%/74.3% by year 80 after vaccination program initiation. For a vaccine coverage of 85%/70%, the reduction in number of varicella cases for 75% and 65% VE-D1 was respectively 71.0%/67.2% by year 30 and 65.8%/61.4% by year 80. When coverage was 75%/60%, the reduction in number of varicella cases was 58.3%/55.8% by year 30 and 54.8%/51.6% by year 80 for VE-D1 of 75% and 65%, respectively. CONCLUSIONS The coverage of varicella vaccination is an important factor affecting the number of varicella cases when long term interval between two doses is considered. This is a more influential factor on predicted cases than the first dose efficacy.