To evaluate the complication rates and possible risk factors of biopsy of the prostate, with the aim of improving patient counseling and the safety of the procedure. Biopsy of the prostate has to be a relatively safe procedure and the participants have to be well informed about the possible complications. Within the biopsy protocol of the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer, we evaluated 5802 transrectal ultrasound-guided systematic sextant biopsies. All participants received prophylactic antibiotic therapy. We performed 5802 biopsies. Hematuria lasting longer than 3 days and hematospermia were present after 22.6% and 50.4% of the procedures, respectively. More severe complications were far less frequent. Two hundred participants (3.5%) developed fever after biopsy. Urinary retention was seen 20 times (0.4%), and hospitalization was needed in 27 cases (0.5%). Twenty-five of these men were admitted because of signs of prostatitis and/or urosepsis. Risk factor analyses revealed that an earlier episode of prostatitis was significantly associated with hospital admission and pain after biopsy. Characteristics of prostatic hyperplasia, such as prostate volume, transition zone volume/total prostate volume ratio, and a higher International Prostate Symptom Score, were all predictors of urinary retention. Minor complications are frequently seen but major complications are rare after prostate biopsy. Assessment of the risk factors before biopsy can help to improve the adequacy of counseling, and precautionary measures can be taken to minimize the risk of complications after the procedure. Transrectal ultrasound-guided sextant biopsy remains a safe procedure for the diagnosis of prostate cancer within the general population.