When in-vitro fertilization (IVF) is used for severe male infertility, the zona pellucida constitutes a major barrier to sperm-oocyte interaction, a barrier that may, in principle, be overcome by micro-injecting one or more spermatozoa into the sub-zonal perivitelline space ('sub-zonal insemination' or SZI). We have defined suitable patients for SZI as having 'extreme' male factor in that they have either shown a failure of fertilization in previous IVF cycles or had < 50 000 motile spermatozoa recoverable after semen preparation. (This is distinct from those with only 'severe' male factor in whom sufficient (> 50 000) motile spermatozoa could be recovered from a semen preparation.) A total of 213 SZI cycles were performed at Sydney IVF in the 4 year period September 1988 to September 1992, for extreme male factor patients with previous IVF failures or extremely low sperm numbers for whom SZI was the first option (about two-thirds and one-third of cases respectively). A total of 138 embryo transfers are reported, producing 20 clinical pregnancies after performing SZI on 1899 oocytes. One patient miscarried at 12 weeks gestation and there have been nine normal deliveries (so far) of 10 healthy infants. The first delivery was in February 1990. One pregnancy was achieved in the only patient in whom spermatozoa were obtained by epididymal aspiration, and transfer of three cryopreserved embryos in another patient resulted in a singleton pregnancy. Of the 492 oocytes fertilized, 282 had two pronuclei (57.3%) and normal embryos were transferred in 138/213 (64.8%) treatment cycles, giving an overall pregnancy rate of 14.5% per embryo transfer or 9.4% per cycle.(ABSTRACT TRUNCATED AT 250 WORDS)