Our purpose was to assess the effect of reader experience, fatigue, and scan findings on interpretation time for CT colonography. Nine radiologists (experienced in CT colonography); nine radiologists and ten technicians (both groups trained using 50 validated examinations) read 40 cases (50% abnormal) under controlled conditions. Individual interpretation times for each case were recorded, and differences between groups determined. Multi-level linear regression was used to investigate effect of scan category (normal or abnormal) and observer fatigue on interpretation times. Experienced radiologists (mean time 10.9 min, SD 5.2) reported significantly faster than less experienced radiologists and technicians; odds ratios of reporting times 1.4 (CI 1.1, 1.8) and 1.6 (1.3, 2.0), respectively (P≤0.001). Experienced and less-experienced radiologists took longer to report abnormal cases; ratio 1.2 (CI 1.1,1.4, P<0.001) and 1.2 (1.0, 1.3, P=0.03), respectively. All groups took 70% as long to report the final five cases as they did with an initial five; ratio 0.7 (CI 0.6 to 0.8), P<0.001. For technicians only, accuracy increased with longer reporting times (P=0.04). Experienced radiologists report faster than do less-experienced observers and proportionally spend less time interpreting normal cases. Technicians who report more slowly are more accurate. All groups reported faster as the study period progressed.