Proniosomal gels or solutions of flurbiprofen were developed based on span 20 (Sp 20), span 40 (Sp 40), span 60 (Sp 60), and span 80 (Sp 80) without and with cholesterol. Nonionic surfactant vesicles (niosomes) formed immediately upon hydrating proniosomal formulae. The entrapment efficiency (EE%) of flurbiprofen (a poorly soluble drug) was either determined by exhaustive dialysis of freshly prepared niosomes or centrifugation of freeze-thawed vesicles. The influence of different processing and formulation variables such as surfactant chain length, cholesterol content, drug concentration, total lipid concentration, negatively or positively charging lipids, and the pH of the dispersion medium on flurbiprofen EE% was demonstrated. Also, the release of the prepared niosomes in phosphate buffer (pH 7.4) was illustrated. Results indicated that the EE% followed the trend Sp 60 (C(18))>Sp 40 (C(16))>Sp 20 (C(12))>Sp 80 (C(18)). Cholesterol increased or decreased the EE% depending on either the type of the surfactant or its concentration within the formulae. The maximum loading efficiency was 94.61% when the hydrating medium was adjusted to pH 5.5. Increasing total lipid or drug concentration also increased the EE% of flurbiprofen into niosomes. However, incorporation of either dicetyl phosphate (DCP) which induces negative charge or stearyl amine (SA) which induces positive charge decreased the EE% of flurbiprofen into niosomal vesicles. Finally, in vitro release data for niosomes of Sp 40 and Sp 60 showed that the release profiles of flurbiprofen from niosomes of different cholesterol contents is an apparently biphasic release process. As a result, this study suggested the potential of proniosomes as stable precursors for the immediate preparation of niosomal carrier systems.