I have looked for a definite answer to this and have not found one. I played my amp the other night with no problems, but last night as I turned on the amp it just died on me as soon as I turned the standby off. There was no noise, pops, crackles, fizzes. It just turned off. I checked the main fuse and it was blown. I have not had any issues with tubes and they have not shown any signs of wearing out. I made sure my amp was connected to the cab correctly (remember i have had this rig for 8 years) and that I had a speaker cable rather than a guitar cable. I found online there could be issues with impedence and what not. I took the back off of my cab and noticed that a positive lead on one of my v30's became disconnected. I thought, 'Could it be?" So I reconnected it and replaced the fuse and the amp worked as advertised. I played for an hour or so and no problems yet. Could it be that the discoonnected positive lead on one speaker caused it to blow a main fuse?
The most common problem for main fuse blowing is a fault in the power supply but this would blow again if you replaced the fuse, as you replaced the fuse and the amplfiier worked this would suggest it is possibly one of your power valves.
Having the speaker lead disconnected is unlikely to blow a main fuse more probably the HT fuse.
Just ran across this....If anyone is still having an issue...if your fuse doesn’t blow...measure pin #5, on the 4 power tubes....run it with standby in “operate” mode....measure every 5 to 10 minutes....and leave the meter connected to and tubes pin 5 just to see if it varies....you should see betweeen -41 vdc & -45vdc.....If it jumps up to the 100’s....your board has the famous Drift issue.....Blowing main fuse...check caps on 120v input board....then check the 1 nF caps where the pink and purple wires attach to the board.....old ceramic caps might even crumble when touched.....put new ones or upstate to the blue caps which can handle more voltage than you’ll ever see in any amp !