To evaluate the planning target volume (PTV) margins for prostate cancer patients treated with initial intensity-modulated radiation therapy (IMRT) to pelvic lymph nodes and a proton boost to the prostate using cone-beam computed tomography (CBCT) and radiographs as image guidance. We analyzed data from prostate patients (n = 15) treated with initial pelvic IMRT and a proton boost to the prostate. CBCT and 2-dimensional (2D) radiographs were used for IMRT and proton pre-treatment alignments, respectively. Translations from bony-matching, implanted marker seed matching, and seed-bony differences were obtained from CBCTs. Pretreatment and post-treatment 2D radiographs were analyzed for residual setup errors and intrafractional organ motion. PTV margins of prostate and pelvic lymph nodes for seed-matching, bony-matching and the skin mark-matching approach were obtained using 2.5 * Σ + 0.7 * σ formula, where Σ is the systematic error and σ is the random error summed in quadrature of various error components. For the seed-matching approach, the prostate margins were 1.5 mm, 3.5 mm, and 2.7 mm for the left-right (LR), superior-inferior (SI), and anterior-posterior (AP) directions, respectively; pelvic lymph node margins were 2.3 mm, 7.1 mm, and 7.0 mm. For the bony-matching approach, the prostate margins were 2.7 mm, 7.8 mm, and 7.5 mm for the LR, SI, and AP directions, respectively; pelvic lymph node margins were 0.7 mm, 1.5 mm, and 1.4 mm. For the skin mark-matching approach, the prostate margins were 7.6 mm, 13.4 mm, and 11.4 mm for the LR, SI, and AP directions, respectively; pelvic lymph node margins were 8.2 mm, 12.6 mm, and 12.3 mm. The seed-matching approach, as compared to the bony-matching approach, reduced prostate margins, which may in turn reduce dose to the bladder and rectum at the expense of increased but acceptable margins for the pelvic lymph nodes.