A comparative study of the signal acquisition from straight fiber and tapered optical fibers has been analyzed theoretically for the design of an evanescent wave fiber optic immunosensor. It has been shown that tapered optical fibers have higher sensitivity compared to straight fibers. Among the tapered fibers combination tapered fibers were also found to have higher sensitivity than continuous tapered fibers. Theoretical analysis indicates that an increase in signal is a result of three factors, namely, V number matching, an increase in evanescent absorption by the fluorescent medium, and an increase in fluorescence emission coupling into the fiber. Maximum sensitivity is obtained when the radius of the fiber is reduced to the V number matching radius within 1 cm from the start of the taper with rest of the fiber remaining untapered. Also, a higher signal level is obtained when the launching light fills the numerical aperture determined by the tapering ratio of the fiber.