Interstitially injected immuno-poly(ethyleneglycol)-liposomes (immuno-PEG-liposomes) can penetrate the thin-walled and fenestrated lymphatic microvessels and are subsequently conveyed to the regional lymph nodes. The exposed Fc region of coupled antibodies on the liposome surface facilitates vesicular recognition and clearance by lymph node macrophages via the Fc receptor. This limits immuno-PEG-liposome targeting to non-macrophage elements of the lymph nodes. We have evaluated the effect of antibody-coupling procedures to surface-exposed PEG chains with the aim of designing immuno-PEG-liposomes that avoid capture by the lymph node macrophages following interstitial injection. Non-specific IgG was oxidized through the addition of sodium periodate for coupling to hydrazine-PEG(2000)-phospholipid incorporated into liposomal bilayer. For comparison, IgG was also coupled to N-(4'-(4''-maleimidophenyl)butyroyl)-phosphatidylethanolamine (MPB-PE) or MPB-PEG(2000)-DSPE-bearing liposomes. The lymphatic fate of the engineered vesicles was followed following interstitial injection. Antibody coupling to MPB-PE and MPB-PEG(2000)-DSPE-bearing liposomes generated random exposure of IgG and favoured macrophage recognition. In IgG-hydrazine-PEG(2000)-liposomes, the antibody is coupled via its Fc portion. Although, this was expected to diminish Fc segment exposure to macrophages, rapidly drained IgG-hydrazine-PEG(2000)-liposomes were susceptible to extraction by lymph node macrophage as confirmed by macrophage elimination experiments with clodronate incorporated vesicles. Further studies with peritoneal macrophages have established a role for the scavenger receptor class A-I/II in recognition of the IgG-hydrazine-PEG(2000)-liposomes. Therefore, for efficient targeting of immuno-PEG-liposomes to non-macrophage elements of the regional lymph nodes, other strategies for antibody coupling must be sought and these are discussed.