Calcineurin-inhibitor therapy can lead to renal dysfunction in heart transplantation patients. The novel immunosuppressive (IS) drug sirolmus (Srl) lacks nephrotoxic effects; however, proteinuria associated with Srl has been reported following renal transplantation. In cardiac transplantation, the incidence of proteinuria associated with Srl is unknown. In this study, long-term cardiac transplant patients were switched from cyclosporine to Srl-based IS. Concomitant IS consisted of mycophenolate mofetil ± steroids. Proteinuria increased significantly from a median of 0.13 g/day (range 0–5.7) preswitch to 0.23 g/day (0–9.88) at 24 months postswitch (p = 0.0024). Before the switch, 11.5% of patients had high-grade proteinuria (>1.0 g/day); this increased to 22.9% postswitch (p = 0.006). ACE inhibitor and angiotensin-releasing blocker (ARB) therapy reduced proteinuria development. Patients without proteinuria had increased renal function (median 42.5 vs. 64.1, p = 0.25), whereas patients who developed high-grade proteinuria showed decreased renal function at the end of follow-up (median 39.6 vs. 29.2, p = 0.125). Thus, proteinuria may develop in cardiac transplant patients after switch to Srl, which may have an adverse effect on renal function in these patients. Srl should be used with ACEi/ARB therapy and patients monitored for proteinuria and increased renal dysfunction.