Objectives Particles due to fragmentation present a clear risk to the patient. Reported fragmentation rates vary, and an insertion angle at 45°, as opposed to 90°, has been proposed as a mitigation strategy. So, this study evaluated the fragmentation rates induced by single-use hypodermic needles using different angled penetration techniques. Methods Needles underwent fragmentation testing using two penetration techniques. In method 1, the needle was inserted through the stopper at 45° and rotated to 90° upon exiting the stopper underside, and in method 2 the needle was rotated only after the bevel was fully enveloped by the stopper. Methods were tested with 18, 20, and 22-gauge needles with bevel faced up, down, and sideways. Fragmentation data sets were subjected to ANOVA and a fit to a General Linear Model was attempted to ascertain the significance of needle size, bevel position, and penetration method; p-values less than 0.05 indicated statistical significance. Results Incidence varied from 0 to 49% and depended on the test method. Needles larger than 22-gauge induced fragmentation the most when the bevel was down. The bevel up position induced fragmentation the least. Generation of large fragments designated “cores” depended on all factors examined, and generation of small fragments designated “fragments” depended on all factors except for the penetration method. Conclusions Clinical context and intended application need to be communicated to manufacturers and considered for functional testing when devising end-user recommendations which must reflect a combination of factors.