What's known on the subject? and What does the study add? Even after a negative set of prostate biopsies, the risk of undetected prostate cancer remains clinically significant. Predictive markers of such a risk are undefined. In addition to PSA and PSAD, low prostate volume and %fPSA are interesting time‐varying risk factors and are relevant in biopsy decision‐making. Objective To assess prospectively the time‐varying risk of rebiopsy and of prostate cancer (PCa) detection after an initial negative biopsy protocol. Patients and Methods Over a period of 10 years, 1995 consecutive patients with initially negative biopsies were followed. Rebiopsies were performed in patients who had a persistent suspicion of PCa. Predictive factors for rebiopsy and for PCa detection were tested using univariate, multivariate and time‐dependent models. Results A total of 617 men (31%) underwent at least one rebiopsy after a mean follow‐up of 19 months. PCa detection rates during second, third, and fourth sets of biopsies were 16.7, 16.9 and 12.5%, respectively. The overall rate of detected PCa was 7.0%. The 5‐year rebiopsy‐free and PCa‐free survival rates were 65.9 and 92.5%, respectively. Indications for rebiopsy were more frequently reported in patients having a high prostate‐specific antigen (PSA) level (P = 0.006) or a high PSA density (PSAD; P < 0.001) and in younger patients (P = 0.008). The risk of PCa on rebiopsies was not correlated with age, but significantly increased more than twofold in cases of PSA >6 ng/mL, PSAD >0.15 ng/mL/g, free‐to‐total PSA ratio (%fPSA) <15, and/or prostate volume <50 mL. Time‐dependent analyses were in line with these findings. The main study limitation was the lack of control of the absence of PCa and PSA kinetics in men not rebiopsied. Conclusions The overall risk of detected PCa after an initial negative biopsy was low. In addition to PSA and PSAD, which are well‐used in rebiopsy indications, low prostate volume and %fPSA are interesting time‐varying risk factors for PCa on rebiopsy and could be relevant in biopsy decision‐making.