This paper investigates the effect of a major macroeconomic shock, the Great Depression, on patenting in an innovative region. Cleveland, Ohio, was a vibrant industrial city in the 1920s, a hotbed of inventive activity and small-scale startups in a range of important Second Industrial Revolution industries. One might expect a shock of the magnitude of the Great Depression to have taken a serious toll on inventive activity, especially in a region such as Cleveland’s, where there were so many small firms dependent on external finance. We explore this issue by comparing the career patenting records of two cohorts of Cleveland patentees who obtained a threshold number of inventions during the years 1910-12 and 1928-30 and find remarkably little effect of the Depression on patenting. We then look at the patenting careers of graduates from the Case School of Applied Science. Only when we focus on the students who graduated in the midst of the Depression do we find a significant effect. We conclude that an important negative consequence of the Depression was to prevent a new generation of inventors from forming to carry on the region’s innovative tradition.