Fertilisation with intracytoplasmic sperm injection (ICSI) is a consequence of complex molecular interactions between spermatozoon and oocyte. Disruption of the process obviously prompts a frustrating event called total fertilisation failure (TFF). Up to 3% of ICSI cycles may result in TFF, and brief counselling for subsequent cycle management is indispensable. Within this perspective, ICSI cycles of a centre over a 10-year period were analysed to document TFF cases. Initial TFF after ICSI and subsequent ICSI cycle of the same cases were documented to clarify predictive factors of successful outcomes after initial TFF. In subsequent cycles, assisted oocyte activation (AOA) with calcium ionophore and Hypo-osmotic swelling test (HOST)/pentoxifilline for sperm selection was used. In the current analysis, successful fertilisation was achieved in 85% of the cases with previous TFF. The significant contributing factors for successful fertilisation in the latter cycle were: improved oocyte quantity and better sperm morphology. In conclusion, sporadic TFF event in the first and only cycle is usually a technically modifiable condition, but repeated TFF could indicate possible gamete defects, which might not be overcomed in the next modified ICSI cycle.