The control of image contrast is essential toward optimizing a contrast enhancement procedure in optical coherence tomography (OCT). In this study, the in vivo control of optical contrast in a mouse tumor model with gold nanoshells as a contrast agent is examined. Gold nanoshells are administered into mice, with the injected dosage and particle surface parameters varied and its concentration in the tumor under each condition is determined using a noninvasive theoretical OCT modeling technique. The results show that too high a concentration of gold nanoshells in the tumor only enhances the OCT signal near the tissue surface, while significantly attenuating the signal deeper into the tissue. With an appropriate dosage, IV delivery of gold nanoshells allows a moderate concentration of in tumor to achieve a good OCT signal enhancement with minimal signal attenuation with depth. An increase in the IV dosage of gold nanoshells reveals a corresponding nonlinear increase in their tumor concentration, as well as a nonlinear reduction in the fractional concentration of injected gold nanoshells. Furthermore, this fractional concentration is improved with the use of antiepodermal growth factor receptor (EGFR) surface functionalization, which also reduces the time required for tumor delivery from 6 to 2 h.