Innovative imaging modalities are applied for diagnosing and follow-up of prostate cancer (PCa). To perform authentic targeted biopsies and evaluate prostate changes, it is essential to reliably identify and hit targets in their true anatomical location over time. A newly described image correlation method (Internal Fusion) allows precise correlation of serial transrectal ultrasound (TRUS) images in vitro and vivo. Identifiable morphologic structures such as prostatic calcifications define internal anchor points (Internal Landmarks) to facilitate exact correlation. After verification of Internal Fusion in vitro, 83 patients were included from January to August 2017 with at least one prior series of 5-mm spaced TRUS images stored as computed tomographic (US-CT) online data set. Two experienced operators collected new images in correlation with each cross-section of the previous examinations based on Internal Landmarks. Of the 83 patients, fifty (60%) had prior negative biopsies. Fourteen (17%) wished US-CT targeted biopsies and PCa were detected in 7/14 patients (50%). Overall, accurate imaging correlations were attained in 369/397 slices (93%). In initial and repeat biopsy, 31/31 and 35/35 images could be correlated detecting PCa in 5/8 (63%) and 2/6 patients (33%). The longest observation of prostate changes over time (Trend Monitoring) with accurate image correlation was 8years and 6months. Internal Fusion by Internal Landmarks ensures exact correlation in long-term follow-up. It is possible to precisely monitor trends in prostate tissue changes. In case of PCa suspicion, biopsies could be targeted with high accuracy by Internal Fusion, even over time.