To assess the stability and efficiency of liposomes carrying a phospholipase A2‐sensitive phospholipid‐allocolchicinoid conjugate (aC‐PC) in the bilayer, egg phosphatidylcholine and 1‐palmitoyl‐2‐oleoylphosphatidylglycerol‐based formulations were tested in plasma protein binding, tubulin polymerization inhibition, and cytotoxicity assays. Liposomes L‐aC‐PC10 containing 10 mol. % aC‐PC in the bilayer bound less plasma proteins and were more stable in 50% plasma within 4 h incubation, according to calcein release and FRET‐based assays. Liposomes with 25 mol. % of the prodrug (L‐aC‐PC25) were characterized by higher storage stability judged by their hydrodynamic radius evolution yet enhanced deposition of blood plasma opsonins on their surface according to SDS‐PAGE and immunoblotting. Notably, inhibition of tubulin polymerization was found to require that the prodrug should be hydrolyzed to the parent allocolchicinoid. The L‐aC‐PC10 and L‐aC‐PC25 formulations demonstrated similar tubulin polymerization inhibition and cytotoxic activities. The L‐aC‐PC10 formulation should be beneficial for applications requiring liposome accumulation at tumor or inflammation sites.