Continued range expansion of introduced eastern fox squirrels (Sciurus niger) in the western United States could lead to widespread damage to agricultural crops, facility infrastructures, and displacement of the native western gray squirrel (S. griseus). Because traditional management alternatives may not be feasible in many areas, public interest in the use of immunocontraceptive to control local populations has increased. We evaluated the efficacy of GonaCon™ immunocontraceptive vaccine for controlling eastern fox squirrel reproduction in Davis, California. We administered GonaCon to 33 male and 26 female fox squirrels, and a control substance to 33 males and 24 females. We subsequently compared the reproductive status, health, and serum concentrations of testosterone and progesterone of our treated and control populations. In our treated population, we also measured serum concentrations of antibodies to gonadotropin‐releasing hormone (GnRH). To determine potential side effects of the vaccine, we recorded body weight and body condition of all animals, examined injection sites during each recapture, and observed the treated squirrels in the field for signs of discomfort and impaired mobility. Over 17 months, none of the recaptured GonaCon‐treated females (n = 20) reproduced, compared to 12 of 15 control females. Treated males and females developed sufficient antibodies to GnRH to suppress reproduction, suggesting that GonaCon has the potential to be 100% effective in inhibiting reproduction in both sexes. We also observed a reduction in physical signs of reproductive activity for males (P < 0.001) and in hormone levels of both females (P < 0.001) and males (P < 0.001). Control and GonaCon‐treated animals did not differ in body weight but vaccinated squirrels had poorer body condition scores and exhibited severe injection site abscesses. The abscesses may have been caused by the GnRH conjugate used in GonaCon. In our study, GonaCon was effective in reducing eastern fox squirrel reproduction. Changes in the conjugate or its preparation may reduce the severity of associated injection site reactions. © 2013 The Wildlife Society