The synthetic nonapeptide Val-Gln-Gly-Glu-Glu-Ser-Asn-Asp-Lys corresponding to the amino acid sequence 163-171 of human interleukin-1beta (IL-1beta) has been reported to retain considerable immunostimulatory activity of the native protein without the induction of the inflammatory or pyrogenic responses. Two lipophilic derivatives of this nonapeptide, one having a lauroyl residue (1) and the other having a palmitoyl residue (2) at the N-terminus of the peptide, and a more stable analog carrying D-Val residue at position 1 of the peptide (3) were synthesized with a view to find out if these structural modifications had a favorable effect on in vitro mouse thymocyte proliferation and IL-1 dependent inhibition of A375 cells. We have found that analogs (1) and (2) are active in both the tests like the parent nonapeptide. The lipophilic analog (2) is in fact, effective at a lower dose as compared to the parent nonapeptide in mouse thymocyte proliferation assay. Although the analog (3) has the ability to inhibit A375 cells, it does not stimulate mouse thymocyte proliferation in vitro. The IL-1beta fragment (163-171) and the analog (2) were further compared for their effects on pyrogenicity, blood glucose level, acute phase response and radioprotection. Unlike IL-1beta, its fragment (163-171) and the analog (2) do not induce pyrogenicity and any of the acute phase related changes such as the increase in C-reactive protein and hypoglycemia following their administration in Balb/c mice. We have found that 40% of animals treated with analog (2) survive more than 21 days after lethal irradiation as compared to 20% survivors in groups treated with recombinant IL-1beta or its nonapeptide fragment (163-171), under conditions when all the control animals died within 10 days. This study may help in designing small peptides which may be more effective and stable.