Recently, surface enhanced Raman spectroscopy (SERS)-active photonic crystal fiber (PCFs) probes have gained great interest for biosensing applications due to the tremendous advantages it has over the conventional planar substrate based SERS measurements, with improvements on the detection sensitivity and reliability in measurements. So far, two main approaches were employed to get the analyte molecule in the vicinity of nanoparticles (NPs) inside PCFs in order to achieve the SERS effect. In the first case, analyte and NPs are pre-mixed and injected inside the holes of the PCF prior to the measurement. In the second approach, controlled anchoring of the NPs inside the inner walls of the PCF was achieved prior to the incorporation of the analyte. Although many studies have been conducted using one configuration or the other, no clear trend is emerging on which one would be the best suited for optimizing the biosensing properties offered by SERS active-PCF. In this paper, we investigate the performances of both configurations along with their interplays with the core size of the PCF probe. We have fabricated several samples of a standard PCF design with different core sizes, and SERS measurements of a standard Raman-active molecule are realized in the same conditions for enabling direct comparisons of the SERS intensity and measurement reliabilities between each configuration, yielding clear directions on the optimization of the SERS-active PCF probe. We envision that this study will pave the way for next-generation clinical biosensors for body fluid analysis, as it exhibits high sensitivity and excellent reliability.