To control an outbreak of invasive meningococcal disease (IMD) among men who have sex with men (MSM) in New York City, the New York City Department of Health and Mental Hygiene recommended vaccination of all HIV-infected MSM and at-risk HIV-uninfected MSM in October 2012. A decision-analytic model estimated the cost-effectiveness of meningococcal vaccination compared with no vaccination. Model inputs, including IMD incidence of 20.5 per 100,000 HIV-positive MSM (42% fatal) and 7.6 per 100,000 HIV-negative MSM (20% fatal), were from Department of Health and Mental Hygiene reported data and published sources. Outcomes included costs (2012 US dollars), IMD cases averted, IMD deaths averted, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs; $/QALY). Scenarios with and without herd immunity were considered, and sensitivity analyses were performed on key inputs. Compared with no vaccination, the targeted vaccination campaign averted an estimated 2.7 IMD cases, 1.0 IMD deaths, with an ICER of $66,000/QALY when herd immunity was assumed. Without herd immunity, vaccination prevented 1.1 IMD cases, 0.4 IMD deaths, with an ICER of $177,000/QALY. In one-way sensitivity analyses, variables that exerted the greatest influence on results in order of effect were the magnitude of herd immunity, IMD case fatality ratio, and IMD incidence. In probabilistic sensitivity analyses, at a cost-effectiveness threshold of $100,000/QALY, vaccination was preferred in 97% of simulations with herd immunity and 20% of simulations without herd immunity. Vaccination during an IMD outbreak among MSM with and without HIV infection was projected to avert IMD cases and deaths and could be cost-effective depending on IMD incidence, case fatality, and herd immunity.