We identified factors that predict return to part-time and full-time work and resumption of unlimited physical activity following open radical retropubic prostatectomy. Between July 1, 2002 and February 28, 2005, 537 men with clinically localized prostate cancer underwent open radical retropubic prostatectomy, as performed by a single surgeon. Intraoperative, perioperative and postoperative parameters were recorded in real time and entered into a database. An assessment was made 1 and 3 months postoperatively regarding time to return to work and unrestricted physical activity. Of the men 50% returned to part-time and full-time work, and unrestricted activity within 14, 21 and 30 days after discharge home, respectively. Patient age and hematocrit at hospital discharge significantly predicted return to part-time and full-time work, and unlimited physical activity. The number of days that the urinary catheter was indwelling was also associated with return to part-time work. Occupation (blue vs white collar) and marital status were also associated with return to full-time work. In the multivariate model a unit increase in hematocrit decreased the time to return to part-time and full-time work, and unrestricted physical activity by 0.50, 0.60 and 0.59 days, respectively. Men with discharge hematocrit greater than 32% were 1.57 (p = 0.059), 1.65 (p = 0.041) and 2.03 (p = 0.002) times more likely to return to part-time and full-time work, and unlimited activity before 14, 21 and 30 days, respectively. Overall models were developed that accounted for 9.4%, 14.0% and 4.0% of the time to return to part-time work, full-time work and unrestricted physical activity, respectively. Efforts to increase discharge hematocrit by minimizing intraoperative blood loss or using preoperative blood management strategies and earlier removal of the urinary catheter have a favorable impact on the return to work and physical activity.