Gradient high-performance liquid chromatography (HPLC) and gas chromatography were applied as screening methods for determination of impurities in fluoxetine hydrochloride drug substances and formulated products from multiple sources. Nuclear magnetic resonance spectroscopy was also used for identification of excipients and some residual solvents. Thirty potential impurities and excipients were investigated. Several impurities were observed in generic products using gradient HPLC that were not detected with isocratic pharmacopeial methods for fluoxetine hydrochloride. Analysis of drug substance samples and capsule formulations from many different suppliers showed a wide variation in quality which, in many cases, would go undetected using isocratic methods. The quality of the innovator's product and some generic samples was high, but many generic samples contained high levels of impurities. A new impurity, N-benzyl fluoxetine, was observed in some generic samples at levels as high as 0.9%. The gradient HPLC method was also used for stability studies and established that generic capsules formulated with lactose were less stable under accelerated conditions than those formulated without lactose.