diff --git a/ports/stm32/powerctrlboot.c b/ports/stm32/powerctrlboot.c
index 206b19b750..880e43e04c 100644
--- a/ports/stm32/powerctrlboot.c
+++ b/ports/stm32/powerctrlboot.c
@@ -154,12 +154,23 @@ void SystemClock_Config(void) {
 
 #elif defined(STM32WB)
 
+#include "stm32wbxx_ll_hsem.h"
+
+// This semaphore protected access to the CLK48 configuration.
+// CPU1 should hold this semaphore while the USB peripheral is in use.
+// See AN5289 and https://github.com/micropython/micropython/issues/6316.
+#define CLK48_SEMID (5)
+
 void SystemClock_Config(void) {
     // Enable the 32MHz external oscillator
     RCC->CR |= RCC_CR_HSEON;
     while (!(RCC->CR & RCC_CR_HSERDY)) {
     }
 
+    // Prevent CPU2 from disabling CLK48.
+    while (LL_HSEM_1StepLock(HSEM, CLK48_SEMID)) {
+    }
+
     // Use HSE and the PLL to get a 64MHz SYSCLK
     #define PLLM (HSE_VALUE / 8000000) // VCO input is 8MHz
     #define PLLN (24) // 24*8MHz = 192MHz