This study compared the tumor content, DNA yield, and NGS sequencing coverage of 100 matched FNA and CNB specimens. Matched image-guided CNB and FNA specimens from 17 adenocarcinomas, four carcinomas not specified, two squamous cell carcinomas, and one melanoma. Two to three FNA specimens were obtained using 20-25 G needles under computed tomography (CT) or ultrasound guidance with a 17-19 G guide needle. Three to four cores were obtained using the guide needle with a 16-20 G needle. The FNA was obtained first for most tumors but the CNB was obtained first for subcentimeter tumors. FNA specimens were smeared and Diff-Quik and Papanicolaou stained. CNB slides were prepared and H&E stained. Tumor fraction was determined independently by two cytopathologists and then reviewed together in cases with >10% discordance. DNA was extracted from tumor-enriched areas of smears and FFPE sections using PicoPure. DNA was quantified using Qubit. NGS was conducted on an Ion Torrent using the Ampliseq Cancer panel primers.