Instructions to resolve the following issue should always be verified by the vendor (Cisco) support team prior to implementation:
The Cisco IronPort appliance will block outbound SMTP traffic from a Project Insight application even if IronPort is configured to allow relay for your SMTP server which is used as Project Insight's relay. For example, IronPort allows relay from your Microsoft Exchange server to send to any address and Project Insight is configured to use your Microsoft Exchange SMTP for relay. Email from MS Outlook users sending through Exchange may send to any outside email address successfully, but Project Insight email to addresses outside of your domain may still get blocked.
You will need to add the Project Insight server to the IronPort Relaylist Sender Group in the Host Access Table (HAT) in order to fix this problem. Please consult with your Cisco support team in order to confirm this requirement and for the specific instructions relevant to your IronPort model and firmware.