We have investigated the topography of polyHEMA coated culture substrates by scanning electron microscopy, and quantitatively assessed their effect upon the spreading activity of mammalian cells. Results indicate a clear correlation between cell spreading activity and polymer film discontinuity. Preparation of polyHEMA films on modified tissue culture substrates has allowed direct investigation of the role of the underlying substrate in regulating cell spreading, and confirms that apparent modulation of cell spreading by polyHEMA reflects increasing expression of the coated surface. We have further employed a spinning technique by which films of precise thickness, down to 0.01 micron, may be produced on coverslips. All polyHEMA coatings prepared in this way are smooth and complete. They do not allow cell attachment at any thickness. We conclude that polyHEMA is non-adhesive for mammalian cells.