This became a particular concern in the 1990s, when Microsoft gained market dominance in desktop operating systems and office suites. The users of Microsoft software are especially vulnerable to the spread of viruses.

Microsoft software is targeted by virus writers due to their desktop dominance, and is often criticized for including many errors and holes for virus writers to exploit. Integrated and non-integrated Microsoft applications such as Microsoft Office and applications with scripting languages with access to the file system (for example Visual Basic Script (VBS), and applications with networking features) are also particularly vulnerable.

Although Windows is by far the most popular operating system for virus writers, some viruses also exist on other platforms. Any operating system that allows third-party programs to run can theoretically run viruses. Some operating systems are less secure than others. Unix-based OS's (and NTFS-aware applications on Windows NT based platforms) only allow their users to run executables within their own protected memory space.

Windows and Unix have similar scripting abilities, but while Unix natively blocks normal users from having access to make changes to the operating system environment, older copies of Windows such as Windows 95 and 98 do not. In 1997, when a virus for Linux was released – known as "Bliss" – leading antivirus vendors issued warnings that Unix-like systems could fall prey to viruses just like Windows.