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In kidney transplantation, BKvirus infection has historically resulted in high rates of graft dysfunction and graft loss. Unlike other opportunistic infections, no therapies have been shown to prevent BK. The purpose of the current study was to evaluate the safety and efficacy of ciprofloxacin for the prevention of BKviremia in kidney transplant recipients. Two hundred kidney transplant recipients were enrolled in a prospective, randomized, double‐blind, placebo‐controlled trial comparing a 3‐month course of ciprofloxacin (n = 133) vs placebo (n = 67) for the prevention of BKviremia. The primary endpoint of BKviremia at month 6 posttransplant occurred in 25 (18.8%) patients in the ciprofloxacin group and 5 (7.5%) in the placebo group (P= .03). Higher rates of BKviremia (23.3% vs 11.9%; P= .06) and BKnephropathy (5.8% vs 1.5%; P= .26) remained at 12 months in the ciprofloxacin group. Ciprofloxacin use was associated with a significantly higher rate of fluoroquinolone‐resistant gram‐negative infections (83.3% vs 50%; P= .04). A 3‐month course of ciprofloxacin was ineffective at preventing BKviremia in kidney transplant recipients and was associated with an increased risk of fluoroquinolone‐resistant infections. Clinical trial registration number: NCT01789203. A 3‐month course of ciprofloxacin beginning within 1 week of transplantation is ineffective for the prevention of BK viremia in kidney transplant recipients and is associated with a significantly higher rate of fluoroquinolone‐resistant gram‐negative infections.