Purpose: We retrospectively studied geometric and dosimetric differences between bony (vertebral body‐based) and soft tissue (GTV‐based) registrations of kilovoltage cone‐beam CT (CBCT) scans for setup and intra‐fraction motion assessment of lung tumor patients receiving hypofractionated image‐guided radiation therapy (HF‐IGRT). Method and Materials: kV‐CBCT scans were acquired before and after HF‐IGRT treatment for ten patients with lung tumors. Pre‐treatment CBCT was registered with planning CT using GTV‐based and bony registrations to determine the treatment isocenter. Isocenter positions and tumor and normal tissue DVHs were compared for the two registration types. Intra‐fraction motion of vertebral bodies and GTV during the approximately half‐hour treatment was determined from pre‐ and post‐treatment CBCTs acquired at the same isocenter. Normal tissue doses were evaluated. Results: The average ±1 SD differences (mm) between isocenter position determined by bony and GTV registrations of planning CT with pre‐treatment CBCT are 1.8±4.2 (left‐right), 0.5±5.7 (ant‐post), 0.6±3.6 (sup‐inf), and 6.4±4.5 (3‐D magnitude). For 6 patients, the distance between the GTV and bony registration isocenters exceeded 5 mm. For the clinical margins used (1 cm GTV‐PTV), coverage and most normal tissue DVHs were minimally affected by registration type except for maximum bronchus dose in one patient that increased by 15 Gy. For 7 patients, GTV and vertebral intrafraction motion determined from the pre‐ and post‐treatment CBCTs, was similar. The average difference was 2.3±1.6 mm with a maximum in one patient of 5 mm. Except for one maximum bronchus dose increase of 18 Gy, normal tissue dose changes were small. Conclusion: Isocenter positions determined by bony and GTV registration can differ by more than 5 mm. This can affect normal tissue doses and, for reduced margins, target coverage. For target dose delivery, GTV‐based registrations are more accurate. Difference in intra‐fraction GTV and vertebral motion is often, but not always, within 3 mm.