The burden of typhoid fever remains high in impoverished settings, and increasing antibiotic resistance is making treatment costly. One strategy for reducing the typhoid morbidity and mortality is vaccination with the Vi polysaccharide vaccine. We use a wealth of new economic and epidemiological data to evaluate the cost-effectiveness of Vi vaccination against typhoid in sites in four Asian cities: Kolkata (India), Karachi (Pakistan), North Jakarta (Indonesia), and Hue (Vietnam). We report results from both a societal as well as a public sector financial perspective.Baseline disease burden estimates in the four areas are: 750 cases per year in two Kolkata neighborhoods (pop 185,000), 84 cases per year in the city of Hue (pop 280,000), 298 cases per year in two sub-districts in North Jakarta (pop 161,000), and 538 cases per year in three squatter settlements in Karachi (pop 102,000). We estimate that a vaccination program targeting all children (2-14.9) would prevent 456, 158, and 258 typhoid cases (and 4.6, 1.6, and 2.6 deaths), and avert 126, 44, and 72 disability-adjusted life years (DALYs) over 3 years in Kolkata, North Jakarta and Karachi, respectively. The net social costs would be US$160 and US$549, per DALY averted in Kolkata and North Jakarta, respectively. These programs, along with a similar program in Karachi, would be considered "very cost-effective" (e.g. costs per DALY averted less than per capita gross national income (GNI)) under a wide range of assumptions. Community-based vaccination programs that also target adults in Kolkata and Jakarta are less cost-effective because incidence is lower in adults than children, but are also likely to be "very cost-effective". A program targeting school-aged children in Hue, Vietnam would prevent 21 cases, avert 6 DALYs, and not be cost-effective (US$3779 per DALY averted) because of the low typhoid incidence there.