Recent research evidences the strong modulatory role of controlled submicron and nanoscale topographies on stem cells fate. To harness these physical surface cues for clinical applications, fabrication of nano- and submicron patterns on clinically relevant biomaterials is greatly needed. In this study, an electron beam lithography method for direct patterning (i.e., no use of masters/imprinting steps) of titanium in the submicron range was developed. The process required the use of an etch mask consisting of a double layer of SiO2 and Al, and the positive AR P-6200.04 electron beam resist. An optimum electron beam dose of 288 μC/cm2 was established for writing the desired patterns. The transfer of the patterns into the titanium substrates was achieved by three different steps: inductively coupled plasma etching of the mask in BCl3/Cl2 followed by reactive ion etching of titanium in SF6/CHF3/O2 and a final wet etch of mask residue. Highly ordered arrays of titanium pits with submicron diameters were produced with high reproducibility. This method provides great versatility in pattern design, direct transfer into titanium and increased control of titanium pattern features at submicron to nanoscale enabling clinically relevant and systematic studies on pattern-induced cellular responses.@en