Photodynamic therapy is an emerging technology and results from the interactions between a photosensitiser, oxygen and light. The delivery of light may either be by surface illumination or by interstitial application. We describe the first clinical application of ultrasound-guided interstitial photodynamic therapy (US-iPDT). A total of 23 treatments with meta-tetra-hydroxyphenyl chlorine (mTHPC) and ultrasound-guided interstitial photodynamic therapy were performed on 21 patients with various conditions at the Head & Neck Centre, University College London Hospital. The needles could be clearly identified during insertion in all 23 treatments, and it was possible to guide parallel needle insertions using ultrasound. Although the resolution of ultrasound is not as high as that of other imaging modalities [i.e. computed tomography (CT) and magnetic resonance imaging (MRI)] it was satisfactory in identifying the centre and the peripheries of the pathological lesions. Ultrasound is very easy to perform, non-invasive, relatively inexpensive, quick, convenient, non-ionising, suited to the imaging of soft tissues and does not cause any discomfort. Ultrasound can be used to guide 'real-time' photodynamic therapy in deep-seated tumours and other malformations and can augment the information from other imaging modalities without affecting the patient's treatment outcome.