Purpose We hypothesized that bone SPECT combined with multiplanar reconstructed CT can identify and target the pain-inducing focus in the foot and can be used to successfully guide anaesthetic infiltrations. Therefore we prospectively investigated feasibility and predictive value of bone SPECT/CT for image guided diagnostic infiltrations in patients with chronic foot pain. Methods All patients received a standardized bone SPECT/CT of both feet. The scintigraphically most active structures were subsequently infiltrated with local anaesthetics under CT-guidance. The pre- and post-infiltration pain intensity was measured using the visual analogue scale (VAS). Then, we assessed (i) the agreement on pain originating structures determined by standard clinical assessment versus SPECT/CT and (ii) the predictive value of SPECT-CT in groups with and without agreement. Results 27 of 30 participants reported a pain reduction on VAS of 50% or more, resulting in a response rate of 90%. When assessing the agreement on pain initiating structures determined by standard clinical assessment versus SPECT/CT, we found a disagreement in 16 of 30 (53%) cases. Particularly, disagreement appeared in all 9 participants with symptoms located in the mid-foot (100%). In participants with hind-foot pathology, disagreement was found in 7 of 21 cases (33%). Conclusion The present study shows the feasibility of 99mTc-DPD-SPECT/CT guided infiltration of osseous structures of patients with chronic foot pain. 99mTc-DPD-SPECT/CT had a higher predictive value on the clinical outcome than the clinical assessment. In the clinical setting 99mTc-DPD-SPECT/CT might overrule the clinical assessment in case of disagreement on the target lesion.