Cylindrical light diffusers (CLDs) are often employed for the treatment of large tumors by interstitial photodynamic therapy (iPDT) and photoimmunotherapy (PIT), which involves careful treatment planning to maximize therapeutic dose coverage while minimizing the number of CLDs used. There is, however, a lack of general guidelines regarding optimal positioning of CLDs, in particular when they are inserted in parallel to treat head and neck squamous cell cancer (HNSCC). Therefore, the purpose of this study is to determine the CLD-CLD distances maximizing the necrosis for different geometries of CLD positions and shed light on the influence of different optical parameters on this distance, in particular when HNSCCs are treated by interstitial PIT with cetuximab-IR700 using up to seven CLDs. To that end, Monte-Carlo simulations of the light propagation around CLDs inserted perpendicularly in a semi-infinite tumor were performed to determine the volume receiving a fluence larger than a therapeutic threshold. An optimization algorithm was then used to calculate and maximize the necrosed tumor volumes. Tumor optical properties were derived from published data. Our findings suggest that optimal CLD positioning maximizing the volume of necrosed tumor during interstitial PIT for typical HNSCC optical properties corresponds to a CLD-CLD distance between 11.5- and 13-mm. Variations of the absorption and reduced scattering coefficients have the greatest influence on CLD placements, while tissue anisotropy factor, CLD insertion geometry, CLD length, and the angular dependence of the radiance emitted by the CLDs have minimal influence. At first approximation the influence of these optical parameters on optimal CLD-CLD distance are independent. Our data also suggests it is possible to derive new treatment plans using knowledge of previous treatment plans.